Polymorphs of arry-380, a selective her2 inhibitor and pharmaceutical compositions containing them

ABSTRACT

Polymorphs of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine are provided herein. Processes for preparing the polymorphs and pharmaceutical composition comprising the polymorphs are also disclosed.

CROSS-REFERENCE TO RELATED APPLICATION(S)

This application is a Continuation of U.S. application Ser. No.16/942,094, filed Jul. 29, 2022, which is a continuation of U.S.application Ser. No. 16/169,937, filed Oct. 24, 2018, which is aContinuation of U.S. application Ser. No. 15/861,444, filed Jan. 3,2018, now U.S. Pat. No. 10,143,692 which is a Continuation of U.S.application Ser. No. 14/923,172, filed Oct. 26, 2015, now U.S. Pat. No.9,889,134, which is a Continuation of U.S. application Ser. No.14/351,835, filed Apr. 14, 2014, now U.S. Pat. No. 9,168,254, which is a35 U.S.C. § 371 application of PCT/US2012/060138, filed Oct. 12, 2012,which claims priority to U.S. Provisional Application No. 61/606,185,filed Mar. 2, 2012 and 61/547,615, filed Oct. 14, 2011. The entirecontent of these applications is hereby incorporated herein byreference.

BACKGROUND OF THE INVENTION Field of the Invention

Polymorphs ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineare provided herein. Also, pharmaceutical compositions comprisingpolymorphs ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand processes for preparing the polymorphs are provided herein.

Description of the State of the Art

N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine(also called “ARRY-380”), which has the structure:

is a selective ErbB2 (HER2) inhibitor described in WO 2007/059257, whichis incorporated by reference in its entirety.N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diaminehas been tested in human clinical trials for hyperproliferativediseases, particularly cancer (see Koch, Kevin. “ARRY-380: A Selective,Oral HER2 Inhibitor for the Treatment of Solid Tumors.” AmericanAssociation of Cancer Research 102^(nd) Annual Meeting, Apr. 3, 2011;which may also be found at:http://www.arraybiopharma.com/_documents/Publication/PubAttachment462.pdf).

Polymorphism is the occurrence of different crystalline forms of asingle compound and it is a property of some compounds and complexes.Thus, polymorphs are distinct solids sharing the same molecular formula,yet each polymorph may have distinct solid state physical properties.Therefore, a single compound may give rise to a variety of polymorphicforms where each form has different and distinct solid state physicalproperties, such as different solubility profiles, melting pointtemperatures, flowability, dissolution rates and/or different X-raydiffraction peaks. These practical physical characteristics areinfluenced by the conformation and orientation of molecules in the unitcell, which defines a particular polymorphic form of a substance. Due tothe possibility of variable solubility of each polymorph, identifyingthe existence of pharmaceutical polymorphs is essential for providingpharmaceuticals with predictable solubility profiles. It is desirable toinvestigate all solid state forms of a drug, including all polymorphicforms, and to determine the stability, dissolution and flow propertiesof each polymorphic form. Polymorphic forms of a compound can bedistinguished in a laboratory by X-ray diffraction spectroscopy, such asX-ray powder diffraction (“XRPD”), and by other methods, such asinfrared spectrometry. Additionally, polymorphic forms of the same drugsubstance or active pharmaceutical ingredient can be administered byitself or formulated as a drug product (pharmaceutical composition) andare well known in the pharmaceutical art to affect, for example, thesolubility, stability, flowability, tractability and compressibility ofdrug substances and the safety and efficacy of drug products. For more,see Hilfiker, Rolf (ed.), Polymorphism in the Pharmaceutical Industry.Weinheim, Germany: Wiley-VCH 2006.

The discovery of new polymorphic forms of a pharmaceutically usefulcompound provides a new opportunity to improve the performancecharacteristics of a pharmaceutical product. It has now beensurprisingly found that new crystalline forms ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineexist.

SUMMARY OF THE INVENTION

Polymorphic forms ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineare described herein, including Forms A, B, C, D, E, F, G, H, I, J, K,L, M, N, O and P. Additionally, amorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineis described herein. Accordingly, the compounds are useful in thetreatment of hyperproliferative diseases, such as cancer.

Another aspect provides methods of preventing or treating a disease ordisorder modulated by ErbB2, comprising administering to a mammal inneed of such treatment an effective amount of a compound describedherein.

Another aspect provides methods of preventing or treating cancer,comprising administering to a mammal in need of such treatment aneffective amount of a compound described herein, alone or in combinationwith one or more additional compounds having anti-cancer properties.

Another aspect provides a method of treating a hyperproliferativedisease in a mammal comprising administering a therapeutically effectiveamount of a compound described herein to the mammal.

Another aspect provides the use of a compound of this invention in themanufacture of a medicament for the treatment of a hyperproliferativedisease.

Another aspect provides compounds described herein for use in thetreatment of cancer.

Another aspect provides a pharmaceutical composition comprising acompound described herein, and a pharmaceutically acceptable carrier orexcipient.

Another aspect provides processes for preparing compounds describedherein.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a characteristic XRPD scan of Form A.

FIG. 2 shows a characteristic XRPD scan of Form B Methanol.

FIG. 3 shows a characteristic XRPD scan of Form B Ethanol.

FIG. 4 shows a characteristic XRPD scan of Form B Isopropyl Alcohol.

FIG. 5 shows a characteristic XRPD scan of Form B Acetonitrile.

FIG. 6 shows a characteristic XRPD scan of Form B Acetone.

FIG. 7 shows a characteristic XRPD scan of Form B Dichloromethane.

FIG. 8 shows a characteristic XRPD scan of Form B Tetrahydrofuran.

FIG. 9 shows a characteristic XRPD scan of Form B Anhydrous.

FIG. 10 shows a characteristic XRPD scan of Form C.

FIG. 11 shows a characteristic XRPD scan of Form D Ethyl Acetate.

FIG. 12 shows a characteristic XRPD scan of Form D Dioxane.

FIG. 13 shows a characteristic XRPD scan of Form D Acetone.

FIG. 14 shows a characteristic XRPD scan of Form D Propyl Acetate.

FIG. 15 shows a characteristic XRPD scan of Form E.

FIG. 16 shows a characteristic XRPD scan of Form F.

FIG. 17 shows a characteristic XRPD scan of Form G hemi-Tetrahydrofuran.

FIG. 18 shows a characteristic XRPD scan of Form G mono-Tetrahydrofuran.

FIG. 19 shows a characteristic XRPD scan of Form G Isopropyl Acetate.

FIG. 20 shows a characteristic XRPD scan of Form G Methyl IsobutylKetone.

FIG. 21 shows a characteristic XRPD scan of Form H.

FIG. 22 shows a characteristic XRPD scan of Form I.

FIG. 23 shows a characteristic XRPD scan of Form J.

FIG. 24 shows a characteristic XRPD scan of Form K.

FIG. 25 shows a characteristic XRPD scan of Form L.

FIG. 26 shows a characteristic XRPD scan of Form M.

FIG. 27 shows a characteristic XRPD scan of Form N.

FIG. 28 shows a characteristic XRPD scan of Form O.

FIG. 29 shows a characteristic XRPD scan of Form P.

FIG. 30 shows a characteristic XRPD scan of amorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.

FIG. 31 shows a characteristic differential scanning calorimetry (“DSC”)scan of Form A.

FIG. 32 shows a characteristic DSC scan of Form B Methanol.

FIG. 33 shows a characteristic DSC scan of Form B Ethanol.

FIG. 34 shows a characteristic DSC scan of Form B Isopropyl Alcohol.

FIG. 35 shows a characteristic DSC scan of Form B Acetonitrile.

FIG. 36 shows a characteristic DSC scan of Form B Acetone.

FIG. 37 shows a characteristic DSC scan of Form B Dichloromethane.

FIG. 38 shows a characteristic DSC scan of Form B Tetrahydrofuran.

FIG. 39 shows a characteristic DSC scan of Form C.

FIG. 40 shows a characteristic DSC scan of Form D Ethyl Acetate.

FIG. 41 shows a characteristic DSC scan of Form D Dioxane.

FIG. 42 shows a characteristic DSC scan of Form D Acetone.

FIG. 43 shows a characteristic DSC scan of Form D Propyl Acetate.

FIG. 44 shows a characteristic DSC scan of Form E.

FIG. 45 shows a characteristic DSC scan of Form F.

FIG. 46 shows a characteristic DSC scan of Form G hemi-Tetrahydrofuran.

FIG. 47 shows a characteristic DSC scan with a thermal gravimetricanalysis (“TGA”) overlay of Form G mono-Tetrahydrofuran.

FIG. 48 shows a characteristic DSC scan of Form G Isopropyl Acetate.

FIG. 49 shows a characteristic DSC scan of Form G Methyl IsobutylKetone.

FIG. 50 shows a characteristic DSC scan of Form H.

FIG. 51 shows a characteristic DSC scan of Form I.

FIG. 52 shows a characteristic DSC scan of Form K.

FIG. 53 shows a characteristic DSC scan of Form L.

FIG. 54 shows a characteristic DSC scan of Form M.

FIG. 55 shows a characteristic DSC scan of Form N.

FIG. 56 shows a characteristic DSC scan of Form O.

FIG. 57 shows a characteristic DSC scan of Form P.

FIG. 58 shows a characteristic mDSC scan of amorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made in detail to certain embodiments, examples ofwhich are illustrated in the accompanying structures and formulas. Whileenumerated embodiments will be described, it will be understood thatthey are not intended to limit the invention to those embodiments. Onthe contrary, the invention is intended to cover all alternatives,modifications, and equivalents, which may be included within the scopeof the present invention as defined by the claims. One skilled in theart will recognize many methods and materials similar or equivalent tothose described herein, which could be used in the practice of thepresent invention. The present invention is in no way limited to themethods and materials described. In the event that one or more of theincorporated literature and similar materials differs from orcontradicts this application, including but not limited to definedterms, term usage, described techniques, or the like, this applicationcontrols.

Definitions

Some alkyl moieties have been abbreviated, for example, methyl (“Me”)and ethyl (“Et”). The abbreviations are sometimes used in conjunctionwith elemental abbreviations and chemical structures, for example,methanol (“MeOH”) or ethanol (“EtOH”). Additional abbreviations usedthroughout the application may include, for example, acetate (“Ac”),acetonitrile (“ACN”), dichloromethane (“DCM”), dimethoxyethane (“DME”),ethyl acetate (“EtOAc”), isopropyl alcohol (“IPA”), methyl acetate(“MeOAc”), methyl isobutyl ketone (“MIBK”), methyl tert-butyl ether(“MTBE”), sodium carboxymethyl cellulose (“NaCMC”) and tetrahydrofuran(“THF”).

The term “about” is used herein to mean approximately, in the region of,roughly, or around. When the term “about” is used in conjunction with anumerical range, it modifies that range by extending the boundariesabove and below the numerical values set forth. In general, the term“about” is used herein to modify a numerical value above and below thestated value by a variance of 20%. In regard to 2θ degrees, the termabout means ±0.2 degrees for polymorphs and +0.6 degrees for isomorphicpolymorphs, unless stated otherwise.

The terms “cancer” and “cancerous” refer to or describe thephysiological condition in mammals that is typically characterized byabnormal or unregulated cell growth. A “tumor” comprises one or morecancerous cells. Examples of cancer include, but are not limited to,carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoidmalignancies. More particular examples of such cancers include squamouscell cancer (e.g., epithelial squamous cell cancer), lung cancerincluding small cell lung cancer, non-small cell lung cancer (“NSCLC”),adenocarcinoma of the lung and squamous carcinoma of the lung, cancer ofthe peritoneum, hepatocellular cancer, gastric or stomach cancerincluding gastrointestinal cancer, pancreatic cancer, glioblastoma,cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma,breast cancer, colon cancer, rectal cancer, colorectal cancer, brain,endometrial or uterine carcinoma, salivary gland carcinoma, kidney orrenal cancer, prostate cancer, vulval cancer, thyroid cancer, hepaticcarcinoma, anal carcinoma, penile carcinoma, skin cancer, includingmelanoma, as well as head and neck cancer.

The term “mammal” means a warm-blooded animal that has or is at risk ofdeveloping a disease described herein and includes, but is not limitedto, guinea pigs, dogs, cats, rats, mice, hamsters, and primates,including humans.

The phrase “pharmaceutically acceptable” indicates that the substance orcomposition is compatible chemically and/or toxicologically, with theother ingredients comprising a formulation, and/or the mammal beingtreated therewith.

The phrase “substantially pure” means the polymorphic form or amorphousmaterial includes less than about 15% by weight of impurities, includingother polymorphic forms. In certain embodiments, the substantially purepolymorphic form or amorphous material includes less than about 10% byweight of impurities, including other polymorphic forms. In certainembodiments, the substantially pure polymorphic form or amorphousmaterial includes less than about 5% by weight of impurities, includingother polymorphic forms. In certain embodiments, the substantially purepolymorphic form or amorphous material includes less than about 1% byweight of impurities, including other polymorphic forms.

The phrases “therapeutically effective amount” or “effective amount”mean an amount of a compound described herein that, when administered toa mammal in need of such treatment, sufficient to (i) treat or preventthe particular disease, condition, or disorder, (ii) attenuate,ameliorate, or eliminate one or more symptoms of the particular disease,condition, or disorder, or (iii) prevent or delay the onset of one ormore symptoms of the particular disease, condition, or disorderdescribed herein. The amount of a compound that will correspond to suchan amount will vary depending upon factors such as the particularcompound, disease condition and its severity, the identity (e.g.,weight) of the mammal in need of treatment, but can nevertheless beroutinely determined by one skilled in the art.

The terms “treat” or “treatment” refer to therapeutic, prophylactic,palliative or preventative measures. Beneficial or desired clinicalresults include, but are not limited to, alleviation of symptoms,diminishment of extent of disease, stabilized (i.e., not worsening)state of disease, delay or slowing of disease progression, ameliorationor palliation of the disease state, and remission (whether partial ortotal), whether detectable or undetectable. “Treatment” can also meanprolonging survival as compared to expected survival if not receivingtreatment. Those in need of treatment include those already with thecondition or disorder, as well as those prone to have the condition ordisorder or those in which the condition or disorder is to be prevented.

Polymorphs

Provided herein are polymorphs ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diaminefreebase, designated Forms A, B, C, D, E, F, G, H, I, J, K, L, M, N, Oand P. Also, provided herein is amorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.Processes for preparing the polymorphs, and pharmaceutical compositionsthereof that are potentially useful in the treatment of diseases,conditions and/or disorders modulated by ErbB2 are also provided.

Many of the polymorphs described herein are solvates. However, some ofthe polymorphs are not solvates, but exist, for example, as anhydrousforms. Also, some of the polymorphs are isomorphic solvate polymorphs(or solvatomorph), which crystallize in the same space group with slightvariation of cell parameters and comprise chemically related structuresbut different elemental composition. In this case, the variation inchemical composition among the isomorphs arises from incorporation ofdifferent water/solvent molecules. Consequently, the isomorphs displaysimilar but non-identical XRPD patterns. For more information onisomorphic polymorphs, see Hilfiker, supra.

Form A

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm A is provided. In certain embodiments, a substantially purecrystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm A is provided. Form A can be distinguished by the XRPD diffractionin FIG. 1 and/or peak assignments of the XRPD diffraction of FIG. 1 inTable 1.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm A, characterized by at least one specific XRPD diffraction peak atabout (2θ degrees±0.2) 20.3 is provided. In a further embodiment, acrystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm A, characterized by at least one specific XRPD diffraction peak atabout (2θ degrees±0.2) 20.278 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm A, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 19.1, 20.3, 21.9, 23.1 and 25.2 is provided. In a furtherembodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm A, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 19.138, 20.278, 21.863, 23.139 and 25.202 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm A, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 16.9, 19.1, 20.3, 21.1, 21.9, 23.1 and 25.2 is provided. Ina further embodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm A, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 16.94, 19.138, 20.278, 21.16, 21.863, 23.139 and 25.202 isprovided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm A, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 12.8, 13.6, 16.3, 16.9, 19.1, 19.4, 20.3, 21.1, 21.9, 23.1,24.5 and 25.2 is provided. In a further embodiment, a crystallinepolymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm A, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 12.78, 13.637, 16.3, 16.94, 19.138, 19.44, 20.278, 21.16,21.863, 23.139, 24.519 and 25.202 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm A which has an XRPD diffraction pattern substantially the same asFIG. 1 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm A which is characterized by XRPD diffraction peaks (2θ degrees±0.2)substantially the same as Table 1 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm A which is characterized by endotherms at about 203.7° C. and240.0° C. is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm A which is characterized by a DSC scan substantially the same asFIG. 31 is provided.

Certain embodiments provide a process for preparingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm A comprising:

(a) mixing amorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand 1:1 EtOH:water; and

(b) recrystallizing the solid to prepare Form A.

In certain embodiments, the mixture in Step (a) is heated. In a furtherembodiment, the mixture in Step (a) is heated to about 50° C.

Form B

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B is provided. In certain embodiments, a substantially purecrystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B is provided. Form B forms isomorphic solvates. Form B can bedistinguished by the representative XRPD diffraction in FIGS. 2 to 9and/or representative peak assignments of the XRPD diffraction of FIGS.2 to 9 in Tables 2 to 9.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B, characterized by XRPD diffraction peaks at about (2θdegrees±0.3) 9.9 and 25.5 is provided. In certain embodiments, acrystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 9.9 and 25.5 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B, characterized by XRPD diffraction peaks at about (2θdegrees±0.3) 9.9, 16.9, 18.0, 20.7 and 25.5 is provided. In certainembodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 9.9, 16.9, 18.0, 20.7 and 25.5 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine Form B, characterized by XRPD diffraction peaks at about (2θdegrees±0.3) 8.4, 9.9, 13.4, 16.9, 18.0, 20.7, 21.2, 24.7 and 25.5 isprovided. In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 8.4, 9.9, 16.9, 18.0, 20.7, 21.2 and 25.5 is provided.

Certain embodiments provide a process for preparingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B comprising:

(a1) mixingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E with a solvent selected from MeOH, or

(a2) mixing amorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand a solvent selected from MeOH, acetone and DCM, or

(a3) mixingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm C/G mixture with a solvent selected from EtOH, or

(a4) mixingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm A with a solvent selected from IPA,

(b) creating a solution with theN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand the solvent, and

(c) recrystallizing the solid to prepare Form B; or

(d1) mixing eitherN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E or amorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand ACN, or

(d2) mixingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G mono-Tetrahydrofuran and THF, and

(e) recrystallizing the solid to prepare Form B; or

(f) heatingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Ethanol, and

(g) recovering the solid to prepare Form B.

In certain embodiments, the solution in Step (b) is created by heatingthe mixture of Step (a2) or (a4) to reflux.

In certain embodiments, the solution in Step (b) is created by usingEtOH as the solvent and heating the mixture of Step (a3) to about 70° C.

In certain embodiments, the heating in Step (f) is done at about 100 toabout 200° C.

In certain embodiments, the solvent in Step (a2) is selected fromacetone and DCM

In certain embodiments,N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E is used in Step (d1).

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Methanol is provided. In certain embodiments, a substantiallypure crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Methanol is provided. Form B Methanol can be distinguished by theXRPD diffraction in FIG. 2 and/or peak assignments of the XRPDdiffraction of FIG. 2 in Table 2.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Methanol, characterized by at least one specific XRPD diffractionpeak at about (2θ degrees±0.2) 10.0 is provided. In a furtherembodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Methanol, characterized by at least one specific XRPD diffractionpeak at about (2θ degrees±0.2) 9.98 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Methanol, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 8.5, 10.0, 13.4, 17.0 and 25.5 is provided. In a furtherembodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Methanol, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 8.46, 9.98, 13.438, 16.981 and 25.519 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Methanol, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 8.5, 10.0, 13.4, 17.0, 18.0, 20.8, 24.7 and 25.5 isprovided. In a further embodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Methanol, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 8.46, 9.98, 13.438, 16.981, 18.042, 20.799, 24.72 and25.519 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Methanol, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 8.5, 10.0, 13.4, 15.8, 17.0, 18.0, 19.7, 20.8, 21.1, 21.6,23.2, 24.7 and 25.5 is provided. In a further embodiment, a crystallinepolymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Methanol, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 8.46, 9.98, 13.438, 15.802, 16.981, 18.042, 19.72, 20.799,21.143, 21.622, 23.161, 24.72 and 25.519 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Methanol which has an XRPD diffraction pattern substantially thesame as FIG. 2 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Methanol which is characterized by XRPD diffraction peaks (2θdegrees±0.2) substantially the same as Table 2 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Methanol which is characterized by an endotherm at about 226.8°C. is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Methanol which is characterized by a DSC scan substantially thesame as FIG. 32 is provided.

Certain embodiments provide a process for preparingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Methanol comprising:

(a) mixing eitherN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E or amorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diaminewith MeOH;

(b) creating a solution with theN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand MeOH; and

(c) recrystallizing the solid to prepare Form B Methanol.

In certain embodiments, the solution in Step (b) is created by heatingthe mixture of Step (a) to reflux.

In certain embodiments,N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E is used in Step (a).

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Ethanol is provided. In certain embodiments, a substantially purecrystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Ethanol is provided. Form B Ethanol can be distinguished by theXRPD diffraction in FIG. 3 and/or peak assignments of the XRPDdiffraction of FIG. 3 in Table 3.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Ethanol, characterized by at least one specific XRPD diffractionpeak at about (2θ degrees±0.2) 25.4 is provided. In a furtherembodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Ethanol, characterized by at least one specific XRPD diffractionpeak at about (2θ degrees±0.2) 25.4 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Ethanol, characterized by XRPD diffraction peaks at about (2θdegrees 0.2) 9.9, 13.3, 20.7, 24.6 and 25.4 is provided. In a furtherembodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Ethanol, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 9.859, 13.3, 20.718, 24.621 and 25.419 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Ethanol, characterized by XRPD diffraction peaks at about (2θdegrees 0.2) 9.9, 13.3, 16.9, 17.9, 19.6, 20.7, 21.5, 23.1, 24.6 and25.4 is provided. In a further embodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Ethanol, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 9.859, 13.3, 16.862, 17.94, 19.602, 20.718, 21.502, 23.08,24.621 and 25.419 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Ethanol which has an XRPD diffraction pattern substantially thesame as FIG. 3 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Ethanol which is characterized by XRPD diffraction peaks (2θdegrees 0.2) substantially the same as Table 3 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Ethanol which is characterized by an endotherm at about 224.8° C.is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Ethanol which is characterized by a DSC scan substantially thesame as FIG. 33 is provided.

Certain embodiments provide a process for preparingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Ethanol comprising:

(a) mixingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm C/G mixture with EtOH;

(b) creating a solution with theN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand EtOH; and

(c) recrystallizing the solid to prepare Form B Ethanol.

In certain embodiments, the solution in Step (b) is created by heatingthe mixture of Step (a) to about 70° C.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Isopropyl Alcohol is provided. In certain embodiments, asubstantially pure crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Isopropyl Alcohol is provided. Form B Isopropyl Alcohol can bedistinguished by the XRPD diffraction in FIG. 4 and/or peak assignmentsof the XRPD diffraction of FIG. 4 in Table 4.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Isopropyl Alcohol, characterized by at least one specific XRPDdiffraction peak at about (2θ degrees±0.2) 16.9 is provided. In afurther embodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Isopropyl Alcohol, characterized by at least one specific XRPDdiffraction peak at about (2θ degrees±0.2) 16.88 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Isopropyl Alcohol, characterized by XRPD diffraction peaks atabout (2θ degrees±0.2) 9.8, 16.9, 17.9, 20.6 and 25.1 is provided. In afurther embodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Isopropyl Alcohol, characterized by XRPD diffraction peaks atabout (2θ degrees±0.2) 9.78, 16.88, 17.899, 20.6 and 25.082 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Isopropyl Alcohol, characterized by XRPD diffraction peaks atabout (2θ degrees±0.2) 9.8, 13.2, 16.9, 17.9, 20.6, 25.1 and 25.3 isprovided. In a further embodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Isopropyl Alcohol, characterized by XRPD diffraction peaks atabout (2θ degrees±0.2) 9.78, 13.201, 16.88, 17.899, 20.6, 25.082 and25.362 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Isopropyl Alcohol, characterized by XRPD diffraction peaks atabout (2θ degrees±0.2) 8.3, 9.8, 13.2, 16.9, 17.9, 20.6, 21.2, 23.0,24.2, 24.6, 25.1 and 25.3 is provided. In a further embodiment, acrystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Isopropyl Alcohol, characterized by XRPD diffraction peaks atabout (2θ degrees±0.2) 8.283, 9.78, 13.201, 16.88, 17.899, 20.6, 21.202,22.981, 24.198, 24.582, 25.082 and 25.362 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Isopropyl Alcohol which has an XRPD diffraction patternsubstantially the same as FIG. 4 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Isopropyl Alcohol which is characterized by XRPD diffractionpeaks (2θ degrees±0.2) substantially the same as Table 4 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Isopropyl Alcohol which is characterized by an endotherm at about222.3° C. is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Isopropyl Alcohol which is characterized by a DSC scansubstantially the same as FIG. 34 is provided.

Certain embodiments provide a process for preparingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Isopropyl Alcohol comprising:

(a) mixingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm A with IPA;

(b) creating a solution with theN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand IPA; and

(c) recrystallizing the solid to prepare Form B Isopropyl Alcohol.

In certain embodiments, the solution in Step (b) is created by heatingthe mixture of Step (a) to reflux.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Acetonitrile is provided. In certain embodiments, a substantiallypure crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Acetonitrile is provided. Form B Acetonitrile can bedistinguished by the XRPD diffraction in FIG. 5 and/or peak assignmentsof the XRPD diffraction of FIG. 5 in Table 5.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Acetonitrile, characterized by at least one specific XRPDdiffraction peak at about (2θ degrees±0.2) 25.7 is provided. In afurther embodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Acetonitrile, characterized by at least one specific XRPDdiffraction peak at about (2θ degrees±0.2) 25.661 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Acetonitrile, characterized by XRPD diffraction peaks at about(2θ degrees±0.2) 10.0, 13.5, 16.9, 24.9 and 25.7 is provided. In afurther embodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Acetonitrile, characterized by XRPD diffraction peaks at about(2θ degrees±0.2) 9.98, 13.46, 16.921, 24.899 and 25.661 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Acetonitrile, characterized by XRPD diffraction peaks at about(2θ degrees±0.2) 10.0, 13.5, 16.9, 21.7, 24.9 and 25.7 is provided. In afurther embodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Acetonitrile, characterized by XRPD diffraction peaks at about(2θ degrees±0.2) 9.98, 13.46, 16.921, 21.741, 24.899 and 25.661 isprovided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Acetonitrile, characterized by XRPD diffraction peaks at about(2θ degrees±0.2) 8.5, 10.0, 13.5, 16.9, 18.1, 19.8, 21.2, 21.7, 23.3,24.9 and 25.7 is provided. In a further embodiment, a crystallinepolymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Acetonitrile, characterized by XRPD diffraction peaks at about(2θ degrees±0.2) 8.46, 9.98, 13.46, 16.921, 18.12, 19.842, 21.239,21.741, 23.319, 24.899 and 25.661 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Acetonitrile which has an XRPD diffraction pattern substantiallythe same as FIG. 5 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Acetonitrile which is characterized by XRPD diffraction peaks (2θdegrees±0.2) substantially the same as Table 5 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Acetonitrile which is characterized by an endotherm at about224.2° C. is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Acetonitrile which is characterized by a DSC scan substantiallythe same as FIG. 35 is provided.

Certain embodiments provide a process for preparingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Acetonitrile comprising:

(a) mixing eitherN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E or amorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand ACN; and

(b) recrystallizing the solid to prepare Form B Acetonitrile.

In certain embodiments,N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E is used in Step (a).

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Acetone is provided. In certain embodiments, a substantially purecrystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Acetone is provided. Form B Acetone can be distinguished by theXRPD diffraction in FIG. 6 and/or peak assignments of the XRPDdiffraction of FIG. 6 in Table 6.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Acetone, characterized by at least one specific XRPD diffractionpeak at about (2θ degrees±0.2) 9.9 is provided. In a further embodiment,a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Acetone, characterized by at least one specific XRPD diffractionpeak at about (2θ degrees±0.2) 9.936 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Acetone, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 9.9, 17.0, 18.0, 24.7 and 25.5 is provided. In a furtherembodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Acetone, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 9.936, 17.02, 17.98, 24.679 and 25.52 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Acetone, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 8.4, 9.9, 13.0, 17.0, 18.0, 19.8, 23.5, 24.7 and 25.5 isprovided. In a further embodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Acetone, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 8.378, 9.936, 13.041, 17.02, 17.98, 19.758, 23.498, 24.679and 25.52 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Acetone which has an XRPD diffraction pattern substantially thesame as FIG. 6 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Acetone which is characterized by XRPD diffraction peaks (2θdegrees±0.2) substantially the same as Table 6 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Acetone which is characterized by an endotherm at about 114.5° C.and 224.1° C. is provided. In certain embodiments, a crystallinepolymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Acetone which is characterized by an endotherm at about 224.1° C.is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Acetone which is characterized by a DSC scan substantially thesame as FIG. 36 is provided.

Certain embodiments provide a process for preparingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Acetone comprising:

(a) mixing amorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand acetone;

(b) creating a solution with theN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand acetone; and

(c) recrystallizing the solid to prepare Form B Acetone.

In certain embodiments, the solution in Step (b) is created by heatingthe mixture of Step (a) to reflux.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Dichloromethane is provided. In certain embodiments, asubstantially pure crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Dichloromethane is provided. Form B Dichloromethane can bedistinguished by the XRPD diffraction in FIG. 7 and/or peak assignmentsof the XRPD diffraction of FIG. 7 in Table 7.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Dichloromethane, characterized by at least one specific XRPDdiffraction peak at about (2θ degrees±0.2) 16.9 is provided. In afurther embodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Dichloromethane, characterized by at least one specific XRPDdiffraction peak at about (2θ degrees±0.2) 16.918 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Dichloromethane, characterized by XRPD diffraction peaks at about(2θ degrees±0.2) 10.0, 13.4, 16.9, 20.7 and 25.6 is provided. In afurther embodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Dichloromethane, characterized by XRPD diffraction peaks at about(2θ degrees±0.2) 9.977, 13.381, 16.918, 20.738 and 25.641 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Dichloromethane, characterized by XRPD diffraction peaks at about(2θ degrees±0.2) 8.4, 10.0, 13.4, 16.9, 18.0, 20.7, 24.8 and 25.6 isprovided. In a further embodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Dichloromethane, characterized by XRPD diffraction peaks at about(2θ degrees±0.2) 8.439, 9.977, 13.381, 16.918, 18.041, 20.738, 24.779and 25.641 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Dichloromethane, characterized by XRPD diffraction peaks at about(2θ degrees±0.2) 8.4, 10.0, 13.4, 16.9, 17.4, 18.0, 18.3, 19.9, 20.7,21.2, 21.8, 23.5, 24.8 and 25.6 is provided. In a further embodiment, acrystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Dichloromethane, characterized by XRPD diffraction peaks at about(2θ degrees±0.2) 8.439, 9.977, 13.381, 16.918, 17.438, 18.041, 18.34,19.899, 20.738, 21.161, 21.802, 23.46, 24.779 and 25.641 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Dichloromethane which has an XRPD diffraction patternsubstantially the same as FIG. 7 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Dichloromethane which is characterized by XRPD diffraction peaks(2θ degrees±0.2) substantially the same as Table 7 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Dichloromethane which is characterized by an endotherm at about129.1° C. and 220.7° C. is provided. In certain embodiments, acrystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Dichloromethane which is characterized by an endotherm at about220.7° C. is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Dichloromethane which is characterized by a DSC scansubstantially the same as FIG. 37 is provided.

Certain embodiments provide a process for preparingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Dichloromethane comprising:

(a) mixing amorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand DCM;

(b) creating a solution with theN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand DCM; and

(c) recrystallizing the solid to prepare Form B Dichloromethane.

In certain embodiments, the solution in Step (b) is created by heatingthe mixture of Step (a) to reflux.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Tetrahydrofuran is provided. In certain embodiments, asubstantially pure crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Tetrahydrofuran is provided. Form B Tetrahydrofuran can bedistinguished by the XRPD diffraction in FIG. 8 and/or peak assignmentsof the XRPD diffraction of FIG. 8 in Table 8.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Tetrahydrofuran, characterized by at least one specific XRPDdiffraction peak at about (2θ degrees±0.2) 25.4 is provided. In afurther embodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Tetrahydrofuran, characterized by at least one specific XRPDdiffraction peak at about (2θ degrees±0.2) 25.44 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Tetrahydrofuran, characterized by XRPD diffraction peaks at about(2θ degrees±0.2) 9.8, 16.7, 17.9, 24.7 and 25.4 is provided. In afurther embodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Tetrahydrofuran, characterized by XRPD diffraction peaks at about(2θ degrees±0.2) 9.819, 16.7, 17.92, 24.66 and 25.44 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Tetrahydrofuran, characterized by XRPD diffraction peaks at about(2θ degrees±0.2) 9.8, 13.4, 16.7, 17.9, 21.4, 24.7 and 25.4 is provided.In a further embodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Tetrahydrofuran, characterized by XRPD diffraction peaks at about(2θ degrees±0.2) 9.819, 13.38, 16.7, 17.92, 21.4, 24.66 and 25.44 isprovided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Tetrahydrofuran, characterized by XRPD diffraction peaks at about(2θ degrees±0.2) 9.8, 13.4, 16.7, 17.9, 21.4, 22.9, 24.7 and 25.4 isprovided. In a further embodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Tetrahydrofuran, characterized by XRPD diffraction peaks at about(2θ degrees±0.2) 9.819, 13.38, 16.7, 17.92, 21.4, 22.92, 24.66 and 25.44is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Tetrahydrofuran which has an XRPD diffraction patternsubstantially the same as FIG. 8 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Tetrahydrofuran which is characterized by XRPD diffraction peaks(2θ degrees±0.2) substantially the same as Table 8 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Tetrahydrofuran which is characterized by an endotherm at about228.5° C. is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Tetrahydrofuran which is characterized by a DSC scansubstantially the same as FIG. 38 is provided.

Certain embodiments provide a process for preparingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Tetrahydrofuran comprising:

(a) mixingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G mono-Tetrahydrofuran and THF; and

(b) recrystallizing the solid to prepare Form B Tetrahydrofuran.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Anhydrous is provided. In certain embodiments, a substantiallypure crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Anhydrous is provided. Form B Anhydrous can be distinguished bythe XRPD diffraction in FIG. 9 and/or peak assignments of the XRPDdiffraction of FIG. 9 in Table 9.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Anhydrous, characterized by at least one specific XRPDdiffraction peak at about (2θ degrees±0.2) 9.9 is provided. In a furtherembodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Anhydrous, characterized by at least one specific XRPDdiffraction peak at about (2θ degrees±0.2) 9.938 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Anhydrous, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 9.9, 13.6, 18.1, 21.5 and 25.5 is provided. In a furtherembodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Anhydrous, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 9.938, 13.641, 18.1, 21.498 and 25.541 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Anhydrous, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 8.4, 9.9, 13.6, 16.8, 17.1, 18.1, 21.2, 21.5, 24.9 and 25.5is provided. In a further embodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Anhydrous, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 8.44, 9.938, 13.641, 16.841, 17.099, 18.1, 21.22, 21.498,24.901 and 25.541 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Anhydrous which has an XRPD diffraction pattern substantially thesame as FIG. 9 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Anhydrous which is characterized by XRPD diffraction peaks (2θdegrees±0.2) substantially the same as Table 9 is provided.

Certain embodiments provide a process for preparingN4-(4-[1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Anhydrous comprising:

(a) heatingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B; and

(b) recovering the solid to prepare Form B Anhydrous.

The Form B in Step (a) may be Form B Methanol, Ethanol, IsopropylAlcohol, Acetonitrile, Acetone, Dichloromethane or Tetrahydrofuran. Incertain embodiments, the Form B in Step (a) is Form B Ethanol. Incertain embodiments, the heating in Step (a) is done at about 100 toabout 200° C.

Form C

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm C is provided. In certain embodiments, a substantially purecrystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm C is provided. Form C can be distinguished by the XRPD diffractionin FIG. 10 and/or peak assignments of the XRPD diffraction of FIG. 10 inTable 10.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm C, characterized by at least one specific XRPD diffraction peak atabout (2θ degrees±0.2) 5.0 is provided. In a further embodiment, acrystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm C, characterized by at least one specific XRPD diffraction peak atabout (2θ degrees±0.2) 5.04 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm C, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 5.0, 14.4, 15.3, 18.4 and 18.9 is provided. In a furtherembodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm C, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 5.04, 14.435, 15.301, 18.437 and 18.902 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm C, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 5.0, 7.2, 10.2, 14.4, 15.3, 15.7, 17.5, 18.4, 18.9, 19.6,22.3 and 24.2 is provided. In a further embodiment, a crystallinepolymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm C, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 5.04, 7.159, 10.159, 14.435, 15.301, 15.717, 17.501,18.437, 18.902, 19.638, 22.34 and 24.181 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm C, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 5.0, 7.2, 10.2, 14.4, 15.3, 15.7, 16.7, 17.5, 18.1, 18.4,18.9, 19.6, 21.1, 21.4, 22.3 and 24.2 is provided. In a furtherembodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm C, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 5.04, 7.159, 10.159, 14.435, 15.301, 15.717, 16.719,17.501, 18.059, 18.437, 18.902, 19.638, 21.08, 21.437, 22.34 and 24.181is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm C which has an XRPD diffraction pattern substantially the same asFIG. 10 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm C which is characterized by XRPD diffraction peaks (2θ degrees±0.2)substantially the same as Table 10 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm C which is characterized by an endotherm at about 253.6° C. isprovided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm C which is characterized by a DSC scan substantially the same asFIG. 39 is provided.

Certain embodiments provide a process for preparingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm C comprising:

(a) mixingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm A and 2-methoxyethanol;

(b) creating a solution with theN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand 2-methoxyethanol; and

(c) recrystallizing the solid to prepare Form C.

In certain embodiments, the solution in Step (b) is created by heatingthe mixture of Step (a) to about 50° C.

Form D

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D is provided. In certain embodiments, a substantially purecrystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D is provided. Form D forms isomorphic solvates. Form D can bedistinguished by the representative XRPD diffraction in FIGS. 11 to 14and/or representative peak assignments of the XRPD diffraction of FIGS.11 to 14 in Tables 11 to 14.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D, characterized by XRPD diffraction peaks at about (2θdegrees±0.3) 8.0 and 12.7 is provided. In certain embodiments, acrystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 8.0 and 12.7 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D, characterized by XRPD diffraction peaks at about (2θdegrees±0.3) 8.0 and 12.6 is provided. In certain embodiments, acrystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 8.0 and 12.6 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D, characterized by XRPD diffraction peaks at about (2θdegrees±0.4) 8.0, 9.8, 11.3, 12.7, 13.9, 16.1, 17.1 and 19.8 isprovided. In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 8.0, 9.8, 11.3, 12.7, 13.9 and 17.1 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D, characterized by XRPD diffraction peaks at about (2θdegrees±0.3) 8.0, 9.8, 11.3, 12.6, 13.9, 16.2, 17.2 and 19.7 isprovided. In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 8.0, 9.8, 11.3, 12.6, 13.9, 17.2 and 19.7 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D, characterized by XRPD diffraction peaks at about (2θdegrees±0.5) 8.0, 9.8, 11.3, 12.7, 13.9, 16.1, 17.1, 19.8, 21.4, 22.1,23.6, 25.3 and 27.5 is provided. In certain embodiments, a crystallinepolymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 8.0, 9.8, 11.3, 12.7, 13.9, 17.2, 22.1 and 25.3 isprovided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D, characterized by XRPD diffraction peaks at about (2θdegrees±0.3) 8.0, 9.8, 11.3, 12.6, 13.9, 16.2, 17.2, 19.7, 21.3, 22.1,23.4, 25.3 and 27.4 is provided. In certain embodiments, a crystallinepolymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 8.0, 9.8, 11.3, 12.6, 13.9, 17.2, 19.7, 22.1 and 25.3 isprovided.

Certain embodiments provide a process for preparingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D comprising:

(a1) mixing amorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand a solvent selected from EtOAc, dioxane and propyl acetate, or

(a2) mixingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E and a solvent selected from acetone and propyl acetate, and

(b) recrystallizing the solid to prepare Form D.

In certain embodiments, the solvent in Step (a1) is selected from EtOAcand dioxane.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Ethyl Acetate is provided. In certain embodiments, asubstantially pure crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Ethyl Acetate is provided. Form D Ethyl Acetate can bedistinguished by the XRPD diffraction in FIG. 11 and/or peak assignmentsof the XRPD diffraction of FIG. 11 in Table 11.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Ethyl Acetate, characterized by at least one specific XRPDdiffraction peak at about (2θ degrees±0.2) 8.0 is provided. In a furtherembodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Ethyl Acetate, characterized by at least one specific XRPDdiffraction peak at about (2θ degrees±0.2) 7.959 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Ethyl Acetate, characterized by XRPD diffraction peaks at about(2θ degrees±0.2) 8.0, 12.7, 16.1, 17.1 and 19.8 is provided. In afurther embodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Ethyl Acetate, characterized by XRPD diffraction peaks at about(2θ degrees±0.2) 7.959, 12.66, 16.099, 17.118 and 19.761 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Ethyl Acetate, characterized by XRPD diffraction peaks at about(2θ degrees±0.2) 8.0, 9.8, 11.3, 12.7, 16.1, 17.1, 19.8 and 23.6 isprovided. In a further embodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Ethyl Acetate, characterized by XRPD diffraction peaks at about(2θ degrees±0.2) 7.959, 9.798, 11.321, 12.66, 16.099, 17.118, 19.761 and23.599 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Ethyl Acetate which has an XRPD diffraction pattern substantiallythe same as FIG. 11 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Ethyl Acetate which is characterized by XRPD diffraction peaks(2θ degrees±0.2) substantially the same as Table 11 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Ethyl Acetate which is characterized by endotherms at about113.0° C. and 240.3° C. is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Ethyl Acetate which is characterized by a DSC scan substantiallythe same as FIG. 40 is provided.

Certain embodiments provide a process for preparingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Ethyl Acetate comprising:

(a) mixing amorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand EtOAc; and

(b) recrystallizing the solid to prepare Form D Ethyl Acetate.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Dioxane is provided. In certain embodiments, a substantially purecrystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Dioxane is provided. Form D Dioxane can be distinguished by theXRPD diffraction in FIG. 12 and/or peak assignments of the XRPDdiffraction of FIG. 12 in Table 12.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Dioxane, characterized by at least one specific XRPD diffractionpeak at about (2θ degrees±0.2) 19.5 is provided. In a furtherembodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Dioxane, characterized by at least one specific XRPD diffractionpeak at about (2θ degrees±0.2) 19.54 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Dioxane, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 7.8, 11.1, 12.5, 19.5 and 23.1 is provided. In a furtherembodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Dioxane, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 7.822, 11.139, 12.5, 19.54 and 23.139 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Dioxane, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 7.8, 11.1, 12.5, 19.5, 21.1, 23.1, 24.0 and 27.2 isprovided. In a further embodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Dioxane, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 7.822, 11.139, 12.5, 19.54, 21.062, 23.139, 24.022 and27.179 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Dioxane, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 7.8, 11.1, 12.5, 17.1, 17.7, 19.5, 21.1, 23.1, 24.0 and27.2 is provided. In a further embodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Dioxane, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 7.822, 11.139, 12.5, 17.135, 17.703, 19.54, 21.062, 23.139,24.022 and 27.179 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Dioxane which has an XRPD diffraction pattern substantially thesame as FIG. 12 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Dioxane which is characterized by XRPD diffraction peaks (2θdegrees±0.2) substantially the same as Table 12 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Dioxane which is characterized by endotherms at about 109.8° C.,238.2° C. and 250.2° C. and an exotherm at about 170.8° C. is provided.In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Dioxane which is characterized by endotherms at about 109.8° C.,238.2° C. and 250.2° C. is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Dioxane which is characterized by a DSC scan substantially thesame as FIG. 41 is provided.

Certain embodiments provide a process for preparingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Dioxane comprising:

(a) mixing amorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand dioxane; and

(b) recrystallizing the solid to prepare Form D Dioxane.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Acetone is provided. In certain embodiments, a substantially purecrystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Acetone is provided. Form D Acetone can be distinguished by theXRPD diffraction in FIG. 13 and/or peak assignments of the XRPDdiffraction of FIG. 13 in Table 13.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Acetone, characterized by at least one specific XRPD diffractionpeak at about (2θ degrees±0.2) 8.0 is provided. In a further embodiment,a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Acetone, characterized by at least one specific XRPD diffractionpeak at about (2θ degrees±0.2) 7.999 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Acetone, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 8.0, 17.1, 21.4, 23.6 and 27.5 is provided. In a furtherembodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Acetone, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 7.999, 17.14, 21.378, 23.561 and 27.482 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Acetone, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 8.0, 13.9, 16.1, 17.1, 19.8, 21.4, 23.6 and 27.5 isprovided. In a further embodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Acetone, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 7.999, 13.923, 16.101, 17.14, 19.761, 21.378, 23.561 and27.482 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Acetone, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 8.0, 9.9, 12.7, 13.9, 16.1, 17.1, 18.0, 19.8, 21.4, 22.1,23.6, 24.3 and 27.5 is provided. In a further embodiment, a crystallinepolymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Acetone, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 7.999, 9.856, 12.681, 13.923, 16.101, 17.14, 18, 19.761,21.378, 22.103, 23.561, 24.259 and 27.482 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Acetone which has an XRPD diffraction pattern substantially thesame as FIG. 13 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Acetone which is characterized by XRPD diffraction peaks (2θdegrees±0.2) substantially the same as Table 13 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Acetone which is characterized by endotherms at about 108.5° C.and 235.1° C. is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Acetone which is characterized by a DSC scan substantially thesame as FIG. 42 is provided.

Certain embodiments provide a process for preparingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Acetone comprising:

(a) mixingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E and acetone; and

(b) recrystallizing the solid to prepare Form D Acetone.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Propyl Acetate is provided. In certain embodiments, asubstantially pure crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Propyl Acetate is provided. Form D Propyl Acetate can bedistinguished by the XRPD diffraction in FIG. 14 and/or peak assignmentsof the XRPD diffraction of FIG. 14 in Table 14.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Propyl Acetate, characterized by at least one specific XRPDdiffraction peak at about (2θ degrees±0.2) 8.0 is provided. In a furtherembodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Propyl Acetate, characterized by at least one specific XRPDdiffraction peak at about (2θ degrees±0.2) 7.999 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Propyl Acetate, characterized by XRPD diffraction peaks at about(2θ degrees±0.2) 8.0, 12.7, 16.1, 17.1 and 19.8 is provided. In afurther embodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Propyl Acetate, characterized by XRPD diffraction peaks at about(2θ degrees±0.2) 7.99, 12.719, 16.121, 17.16 and 19.782 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Propyl Acetate, characterized by XRPD diffraction peaks at about(2θ degrees±0.2) 8.0, 12.7, 16.1, 17.1, 19.8, 23.6 and 27.6 is provided.In a further embodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Propyl Acetate, characterized by XRPD diffraction peaks at about(2θ degrees±0.2) 7.99, 12.719, 16.121, 17.16, 19.782, 23.62 and 27.579is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Propyl Acetate, characterized by XRPD diffraction peaks at about(2θ degrees±0.2) 8.0, 9.8, 12.7, 13.9, 16.1, 17.1, 18.0, 19.8, 21.4,23.6, 24.3 and 27.6 is provided. In a further embodiment, a crystallinepolymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Propyl Acetate, characterized by XRPD diffraction peaks at about(2θ degrees±0.2) 7.99, 9.839, 12.719, 13.903, 16.121, 17.16, 18.021,19.782, 21.42, 23.62, 24.28 and 27.579 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Propyl Acetate which has an XRPD diffraction patternsubstantially the same as FIG. 14 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Propyl Acetate which is characterized by XRPD diffraction peaks(2θ degrees±0.2) substantially the same as Table 14 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Propyl Acetate which is characterized by endotherms at about119.6° C. and 247.7° C. is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Propyl Acetate which is characterized by a DSC scan substantiallythe same as FIG. 43 is provided.

Certain embodiments provide a process for preparingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Propyl Acetate comprising:

(a) mixing eitherN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E or amorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand propyl acetate; and

(b) recrystallizing the solid to prepare Form D Propyl Acetate.

In certain embodiments,N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E is used in Step (a).

Form E

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E is provided. In certain embodiments, a substantially purecrystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E is provided. Form E can be distinguished by the XRPD diffractionin FIG. 15 and/or peak assignments of the XRPD diffraction of FIG. 15 inTable 15.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E, characterized by at least one specific XRPD diffraction peak atabout (2θ degrees±0.2) 16.1 is provided. In a further embodiment, acrystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E, characterized by at least one specific XRPD diffraction peak atabout (2θ degrees±0.2) 16.06 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 8.7, 9.4, 11.9, 16.1 and 23.7 is provided. In a furtherembodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 8.659, 9.353, 11.904, 16.06 and 23.739 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E which has an XRPD diffraction pattern substantially the same asFIG. 15 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E which is characterized by XRPD diffraction peaks (2θ degrees±0.2)substantially the same as Table 15 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E which is characterized by endotherms at about 149.7° C. and253.1° C. is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E which is characterized by a DSC scan substantially the same asFIG. 44 is provided.

Certain embodiments provide a process for preparingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E comprising:

(a) mixing1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methyl-phenyl)amino)quinazolin-6-yl)-3-(1-hydroxy-2-methylpropan-2-yl)thioureain THF under basic conditions;

(b) adding water to the mixture to form an oil ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;

(c) recovering the product asN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E.

In certain embodiments, the basic conditions in Step (a) are provided by2.5N NaOH.

Form F

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm F is provided. In certain embodiments, a substantially purecrystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm F is provided. Form F can be distinguished by the XRPD diffractionin FIG. 16 and/or peak assignments of the XRPD diffraction of FIG. 16 inTable 16.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm F, characterized by at least one specific XRPD diffraction peak atabout (2θ degrees±0.2) 16.6 is provided. In a further embodiment, acrystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm F, characterized by at least one specific XRPD diffraction peak atabout (2θ degrees±0.2) 16.56 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm F, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 14.9, 16.6, 16.9, 19.1 and 21.2 is provided. In a furtherembodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm F, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 14.899, 16.56, 16.92, 19.098 and 21.18 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm F, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 14.9, 16.6, 16.9, 19.1, 21.2 and 22.5 is provided. In afurther embodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm F, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 14.899, 16.56, 16.92, 19.098, 21.18 and 22.537 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm F which has an XRPD diffraction pattern substantially the same asFIG. 16 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm F which is characterized by XRPD diffraction peaks (2θ degrees±0.2)substantially the same as Table 16 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm F which is characterized by endotherms at about 122.7° C., 234.2°C. and 250.5° C. is provided. In certain embodiments, a crystallinepolymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm F which is characterized by endotherms at about 122.7° C. and250.5° C. is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm F which is characterized by a DSC scan substantially the same asFIG. 45 is provided.

Certain embodiments provide a process for preparingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm F comprising:

(a) mixingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E and ethyl acetate; and

(b) recrystallizing the solid to prepare Form F.

Form G

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G is provided. In certain embodiments, a substantially purecrystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G is provided. Form G forms isomorphic solvates. Form G can bedistinguished by the representative XRPD diffraction in FIGS. 17 to 20and/or representative peak assignments of the XRPD diffraction of FIGS.17 to 20 in Tables 17 to 20.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G, characterized by XRPD diffraction peaks at about (2θdegrees±0.4) 7.8 and 23.1 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G, characterized by XRPD diffraction peaks at about (2θdegrees±0.3) 7.8 and 23.2 is provided. In certain embodiments, acrystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G, characterized by XRPD diffraction peak at about (2θ degrees±0.2)7.8 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G, characterized by XRPD diffraction peaks at about (2θdegrees±0.4) 7.8, 11.1 and 23.1 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G, characterized by XRPD diffraction peaks at about (2θdegrees±0.3) 7.8, 11.2 and 23.2 is provided. In certain embodiments, acrystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 7.8 and 11.2 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G, characterized by XRPD diffraction peaks at about (2θdegrees±0.5) 7.8, 8.2, 9.4, 11.1, 16.6, 23.1, 24.1 and 27.8 is provided.In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 7.8, 8.2, 9.4 and 16.6 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G, characterized by XRPD diffraction peaks at about (2θdegrees±0.3) 7.8, 8.1, 9.3, 11.2, 16.6, 23.2, 24.3 and 27.6 is provided.In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 7.8, 8.1, 9.3, 11.2 and 16.6 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G, characterized by XRPD diffraction peaks at about (2θdegrees±0.5) 5.6, 7.8, 8.2, 9.4, 11.1, 12.7, 15.6, 16.6, 20.0, 21.0,23.1, 23.4, 24.1 and 27.8 is provided. In certain embodiments, acrystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 5.6, 7.8, 8.2, 9.4, 12.7 and 16.6 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G, characterized by XRPD diffraction peaks at about (2θdegrees±0.3) 5.6, 7.8, 8.1, 9.3, 11.2, 12.7, 15.7, 16.6, 20.0, 21.2,23.2, 23.5, 24.3 and 27.6 is provided. In certain embodiments, acrystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 5.6, 7.8, 8.1, 9.3, 11.2, 12.7, 16.6 and 21.2 is provided.

Certain embodiments provide a process for preparingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G comprising:

(a1) mixingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G mono-Tetrahydrofuran and 20:80 THF:water, or

(a2) mixing eitherN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E or amorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand a solvent selected from isopropyl acetate and MIBK, and

(b) recrystallizing the solid to prepare Form G; or

(c) mixingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm A and tetrahydrofuran,

(d) creating a solution with theN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand THF, and

(e) recrystallizing the solid to prepare Form G.

In certain embodiments, the solution in Step (d) is created by heatingthe mixture of Step (c) to reflux.

In certain embodiments,N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E is used in Step (a2).

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G hemi-Tetrahydrofuran is provided. In certain embodiments, asubstantially pure crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G hemi-Tetrahydrofuran is provided. Form G hemi-Tetrahydrofuran canbe distinguished by the XRPD diffraction in FIG. 17 and/or peakassignments of the XRPD diffraction of FIG. 17 in Table 17.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G hemi-Tetrahydrofuran, characterized by at least one specific XRPDdiffraction peak at about (2θ degrees±0.2) 23.1 is provided. In afurther embodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G hemi-Tetrahydrofuran, characterized by at least one specific XRPDdiffraction peak at about (2θ degrees±0.2) 23.079 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G hemi-Tetrahydrofuran, characterized by XRPD diffraction peaks atabout (2θ degrees±0.2) 7.7, 11.1, 12.3, 23.1 and 24.1 is provided. In afurther embodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G hemi-Tetrahydrofuran, characterized by XRPD diffraction peaks atabout (2θ degrees±0.2) 7.719, 11.102, 12.281, 23.079 and 24.099 isprovided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G hemi-Tetrahydrofuran, characterized by XRPD diffraction peaks atabout (2θ degrees±0.2) 7.7, 11.1, 12.3, 23.1, 24.1 and 27.5 is provided.In a further embodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G hemi-Tetrahydrofuran, characterized by XRPD diffraction peaks atabout (2θ degrees±0.2) 7.719, 11.102, 12.281, 23.079, 24.099 and 27.503is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G hemi-Tetrahydrofuran which has an XRPD diffraction patternsubstantially the same as FIG. 17 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G hemi-Tetrahydrofuran which is characterized by XRPD diffractionpeaks (2θ degrees±0.2) substantially the same as Table 17 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G hemi-Tetrahydrofuran which is characterized by endotherms atabout 106.1° C. and 232.3° C. is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G hemi-Tetrahydrofuran which is characterized by a DSC scansubstantially the same as FIG. 46 is provided.

Certain embodiments provide a process for preparingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G hemi-Tetrahydrofuran comprising:

(a) mixingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G mono-Tetrahydrofuran and 20:80 THF:water; and

(b) recrystallizing the solid to prepare Form G hemi-Tetrahydrofuran.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G mono-Tetrahydrofuran is provided. In certain embodiments, asubstantially pure crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G mono-Tetrahydrofuran is provided. Form G mono-Tetrahydrofuran canbe distinguished by the XRPD diffraction in FIG. 18 and/or peakassignments of the XRPD diffraction of FIG. 18 in Table 18.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G mono-Tetrahydrofuran, characterized by at least one specific XRPDdiffraction peak at about (2θ degrees±0.2) 23.1 is provided. In afurther embodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G mono-Tetrahydrofuran, characterized by at least one specific XRPDdiffraction peak at about (2θ degrees±0.2) 23.022 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G mono-Tetrahydrofuran, characterized by XRPD diffraction peaks atabout (2θ degrees±0.2) 7.7, 11.1, 12.4, 23.0 and 24.0 is provided. In afurther embodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G mono-Tetrahydrofuran, characterized by XRPD diffraction peaks atabout (2θ degrees±0.2) 7.72, 11.137, 12.401, 23.022 and 24.042 isprovided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G mono-Tetrahydrofuran, characterized by XRPD diffraction peaks atabout (2θ degrees±0.2) 7.7, 8.0, 9.4, 11.1, 12.4, 16.6, 21.0, 23.0,23.4, 24.0 and 27.5 is provided. In a further embodiment, a crystallinepolymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G mono-Tetrahydrofuran, characterized by XRPD diffraction peaks atabout (2θ degrees±0.2) 7.72, 8.003, 9.417, 11.137, 12.401, 16.599,21.017, 23.022, 23.397, 24.042 and 27.482 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G mono-Tetrahydrofuran which has an XRPD diffraction patternsubstantially the same as FIG. 18 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G mono-Tetrahydrofuran which is characterized by XRPD diffractionpeaks (2θ degrees±0.2) substantially the same as Table 18 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G mono-Tetrahydrofuran which is characterized by endotherms atabout 113.2° C. and 232.3° C. is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G mono-Tetrahydrofuran which is characterized by a DSC scansubstantially the same as FIG. 47 is provided.

Certain embodiments provide a process for preparingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G mono-Tetrahydrofuran comprising:

(a) mixingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm A and tetrahydrofuran;

(b) creating a solution with theN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand THF; and

(c) recrystallizing the solid to prepare Form G mono-Tetrahydrofuran.

In certain embodiments, the solution in Step (b) is created by heatingthe mixture of Step (a) to reflux.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G Isopropyl Acetate is provided. In certain embodiments, asubstantially pure crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G Isopropyl Acetate is provided. Form G Isopropyl Acetate can bedistinguished by the XRPD diffraction in FIG. 19 and/or peak assignmentsof the XRPD diffraction of FIG. 19 in Table 19.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G Isopropyl Acetate, characterized by at least one specific XRPDdiffraction peak at about (2θ degrees±0.2) 23.4 is provided. In afurther embodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G Isopropyl Acetate, characterized by at least one specific XRPDdiffraction peak at about (2θ degrees±0.2) 23.438 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G Isopropyl Acetate, characterized by XRPD diffraction peaks atabout (2θ degrees±0.2) 7.8, 8.3, 11.4, 13.2 and 23.4 is provided. In afurther embodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G Isopropyl Acetate, characterized by XRPD diffraction peaks atabout (2θ degrees±0.2) 7.803, 8.299, 11.398, 13.18 and 23.438 isprovided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G Isopropyl Acetate, characterized by XRPD diffraction peaks atabout (2θ degrees±0.2) 7.8, 8.3, 9.4, 11.4, 13.2, 16.6, 23.4 and 24.4 isprovided. In a further embodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G Isopropyl Acetate, characterized by XRPD diffraction peaks atabout (2θ degrees±0.2) 7.803, 8.299, 9.361, 11.398, 13.18, 16.64, 23.438and 24.381 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G Isopropyl Acetate, characterized by XRPD diffraction peaks atabout (2θ degrees±0.2) 7.8, 8.3, 9.4, 11.4, 12.7, 13.2, 16.6, 18.1,19.6, 20.0, 21.7, 23.4, 24.4 and 27.8 is provided. In a furtherembodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G Isopropyl Acetate, characterized by XRPD diffraction peaks atabout (2θ degrees±0.2) 7.803, 8.299, 9.361, 11.398, 12.7, 13.18, 16.64,18.099, 19.639, 19.979, 21.738, 23.438, 24.381 and 27.821 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G Isopropyl Acetate which has an XRPD diffraction patternsubstantially the same as FIG. 19 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G Isopropyl Acetate which is characterized by XRPD diffractionpeaks (2θ degrees±0.2) substantially the same as Table 19 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G Isopropyl Acetate which is characterized by endotherms at about123.3° C., 221.3° C. and 237.0° C. is provided. In certain embodiments,a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G Isopropyl Acetate which is characterized by endotherms at about123.3° C. and 237.0° C. is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G Isopropyl Acetate which is characterized by a DSC scansubstantially the same as FIG. 48 is provided.

Certain embodiments provide a process for preparingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G Isopropyl Acetate comprising:

(a) mixing eitherN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E or amorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand isopropyl acetate; and

(b) recrystallizing the solid to prepare Form G Isopropyl Acetate.

In certain embodiments,N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E is used in Step (a).

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G Methyl Isobutyl Ketone is provided. In certain embodiments, asubstantially pure crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G Methyl Isobutyl Ketone is provided. Form G Methyl Isobutyl Ketonecan be distinguished by the XRPD diffraction in FIG. 20 and/or peakassignments of the XRPD diffraction of FIG. 20 in Table 20.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G Methyl Isobutyl Ketone, characterized by at least one specificXRPD diffraction peak at about (2θ degrees±0.2) 23.3 is provided. In afurther embodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G Methyl Isobutyl Ketone, characterized by at least one specificXRPD diffraction peak at about (2θ degrees 0.2) 23.28 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G Methyl Isobutyl Ketone, characterized by XRPD diffraction peaksat about (2θ degrees±0.2) 7.8, 8.2, 11.2, 16.5 and 23.2 is provided. Ina further embodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G Methyl Isobutyl Ketone, characterized by XRPD diffraction peaksat about (2θ degrees±0.2) 7.78, 8.217, 11.239, 16.503 and 23.28 isprovided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G Methyl Isobutyl Ketone, characterized by XRPD diffraction peaksat about (2θ degrees±0.2) 7.8, 8.2, 9.3, 11.2, 13.1, 16.5, 19.9, 21.4,23.2, 24.6 and 27.8 is provided. In a further embodiment, a crystallinepolymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G Methyl Isobutyl Ketone, characterized by XRPD diffraction peaksat about (2θ degrees±0.2) 7.78, 8.217, 9.298, 11.239, 13.079, 16.503,19.858, 21.442, 23.28, 24.562 and 27.759 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G Methyl Isobutyl Ketone, characterized by XRPD diffraction peaksat about (2θ degrees±0.2) 7.8, 8.2, 9.3, 11.2, 12.3, 12.6, 13.1, 16.5,19.9, 21.4, 23.2, 23.6, 24.6 and 27.8 is provided. In a furtherembodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G Methyl Isobutyl Ketone, characterized by XRPD diffraction peaksat about (2θ degrees±0.2) 7.78, 8.217, 9.298, 11.239, 12.341, 12.575,13.079, 16.503, 19.858, 21.442, 23.28, 23.619, 24.562 and 27.759 isprovided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G Methyl Isobutyl Ketone which has an XRPD diffraction patternsubstantially the same as FIG. 20 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G Methyl Isobutyl Ketone which is characterized by XRPD diffractionpeaks (2θ degrees±0.2) substantially the same as Table 20 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G Methyl Isobutyl Ketone which is characterized by endotherms atabout 102.2° C., 234.8° C. and 251.4° C. is provided. In certainembodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G Methyl Isobutyl Ketone which is characterized by endotherms atabout 234.8° C. and 251.4° C. is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G Methyl Isobutyl Ketone which is characterized by a DSC scansubstantially the same as FIG. 49 is provided.

Certain embodiments provide a process for preparingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G Methyl Isobutyl Ketone comprising:

(a) mixing eitherN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E or amorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand MIBK; and

(b) recrystallizing the solid to prepare Form G Methyl Isobutyl Ketone.

In certain embodiments,N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E is used in Step (a).

Form H

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm H is provided. In certain embodiments, a substantially purecrystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm H is provided. Form H can be distinguished by the XRPD diffractionin FIG. 21 and/or peak assignments of the XRPD diffraction of FIG. 21 inTable 21.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm H, characterized by at least one specific XRPD diffraction peak atabout (2θ degrees±0.2) 11.2 is provided. In a further embodiment, acrystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm H, characterized by at least one specific XRPD diffraction peak atabout (2θ degrees±0.2) 11.18 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm H, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 11.2, 16.1, 19.6, 22.0 and 25.5 is provided. In a furtherembodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm H, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 11.18, 16.08, 19.58, 22.04 and 25.501 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm H which has an XRPD diffraction pattern substantially the same asFIG. 21 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm H which is characterized by XRPD diffraction peaks (2θ degrees±0.2)substantially the same as Table 21 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm H which is characterized by an endotherm at about 231.6° C. isprovided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm H which is characterized by a DSC scan substantially the same asFIG. 50 is provided.

Certain embodiments provide a process for preparingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm H comprising:

(a) mixing amorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand MTBE; and

(b) recrystallizing the solid to prepare Form H.

Form I

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm I is provided. In certain embodiments, a substantially purecrystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm I is provided. Form I can be distinguished by the XRPD diffractionin FIG. 22 and/or peak assignments of the XRPD diffraction of FIG. 22 inTable 22.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm I, characterized by at least one specific XRPD diffraction peak atabout (2θ degrees±0.2) 7.2 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm I, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 7.2, 16.6, 18.3, 22.3 and 23.1 is provided. In a furtherembodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm I, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 7.2, 16.559, 18.303, 22.282 and 23.101 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm I, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 7.2, 12.1, 16.3, 16.6, 18.3, 19.3, 19.5, 20.6, 22.3 and23.1 is provided. In a further embodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm I, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 7.2, 12.117, 16.319, 16.559, 18.303, 19.32, 19.54, 20.641,22.282 and 23.101 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm I which has an XRPD diffraction pattern substantially the same asFIG. 22 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm I which is characterized by XRPD diffraction peaks (2θ degrees±0.2)substantially the same as Table 22 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm I which is characterized by endotherms at about 132.6° C. and236.3° C. and an exotherm at about 183.3° C. is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm I which is characterized by a DSC scan substantially the same asFIG. 51 is provided.

Certain embodiments provide a process for preparingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm I comprising:

(a) mixing amorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand xylene; and

(b) recrystallizing the solid to prepare Form I.

Form J

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm J is provided. In certain embodiments, a substantially purecrystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm J is provided. Form J can be distinguished by the XRPD diffractionin FIG. 23 and/or peak assignments of the XRPD diffraction of FIG. 23 inTable 23.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm J, characterized by at least one specific XRPD diffraction peak atabout (2θ degrees±0.2) 17.0 is provided. In a further embodiment, acrystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm J, characterized by at least one specific XRPD diffraction peak atabout (2θ degrees±0.2) 16.963 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm J, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 4.5, 9.0, 17.0, 18.0 and 18.8 is provided. In a furtherembodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm J, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 4.479, 8.982, 16.963, 18.078 and 18.797 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm J which has an XRPD diffraction pattern substantially the same asFIG. 23 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm J which is characterized by XRPD diffraction peaks (2θ degrees±0.2)substantially the same as Table 23 is provided.

Certain embodiments provide a process for preparingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm J comprising:

(a) mixing eitherN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E or amorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand 2-methoxyethanol; and

(b) recrystallizing the solid to prepare Form J.

In certain embodiments,N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E is used in Step (a).

Form K

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm K is provided. In certain embodiments, a substantially purecrystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm K is provided. Form K can be distinguished by the XRPD diffractionin FIG. 24 and/or peak assignments of the XRPD diffraction of FIG. 24 inTable 24.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm K, characterized by at least one specific XRPD diffraction peak atabout (2θ degrees±0.2) 22.8 is provided. In a further embodiment, acrystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm K, characterized by at least one specific XRPD diffraction peak atabout (2θ degrees±0.2) 22.78 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm K, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 15.8, 17.6, 22.8, 23.0 and 25.7 is provided. In a furtherembodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm K, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 15.797, 17.62, 22.78, 23 and 25.701 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm K, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 13.9, 15.8, 17.6, 19.0, 22.8, 23.0 and 25.7 is provided. Ina further embodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm K, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 13.923, 15.797, 17.62, 18.999, 22.78, 23 and 25.701 isprovided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm K which has an XRPD diffraction pattern substantially the same asFIG. 24 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm K which is characterized by XRPD diffraction peaks (2θ degrees±0.2)substantially the same as Table 24 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm K which is characterized by endotherms at about 119.3° C., 241.2°C. and 253.4° C. and an exotherm at about 171.6° C. is provided. Incertain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm K which is characterized by endotherms at about 241.2° C. and253.4° C. and an exotherm at about 171.6° C. is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm K which is characterized by a DSC scan substantially the same asFIG. 52 is provided.

Certain embodiments provide a process for preparingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm K comprising:

(a) mixing eitherN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E or amorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand DME; and

(b) recrystallizing the solid to prepare Form K.

In certain embodiments,N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E is used in Step (a).

Form L

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm L is provided. In certain embodiments, a substantially purecrystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm L is provided. Form L can be distinguished by the XRPD diffractionin FIG. 25 and/or peak assignments of the XRPD diffraction of FIG. 25 inTable 25.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm L, characterized by at least one specific XRPD diffraction peak atabout (2θ degrees±0.2) 17.0 is provided. In a further embodiment, acrystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm L, characterized by at least one specific XRPD diffraction peak atabout (2θ degrees±0.2) 16.98 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm L, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 14.9, 17.0, 19.0, 21.1 and 22.5 is provided. In a furtherembodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm L, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 14.899, 16.98, 18.958, 21.062 and 22.457 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm L which has an XRPD diffraction pattern substantially the same asFIG. 25 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm L which is characterized by XRPD diffraction peaks (2θ degrees±0.2)substantially the same as Table 25 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm L which is characterized by endotherms at about 120.4° C. and251.6° C. and an exotherm at about 202.3° C. is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm L which is characterized by a DSC scan substantially the same asFIG. 53 is provided.

Certain embodiments provide a process for preparingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm L comprising:

(a) mixing eitherN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E or amorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand MeOAc; and

(b) recrystallizing the solid to prepare Form L.

In certain embodiments,N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E is used in Step (a).

Form M

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm M is provided. In certain embodiments, a substantially purecrystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm M is provided. Form M can be distinguished by the XRPD diffractionin FIG. 26 and/or peak assignments of the XRPD diffraction of FIG. 26 inTable 26.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm M, characterized by at least one specific XRPD diffraction peak atabout (2θ degrees±0.2) 9.0 is provided. In a further embodiment, acrystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm M, characterized by at least one specific XRPD diffraction peak atabout (2θ degrees±0.2) 8.982 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm M, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 9.0, 15.1, 20.7, 23.1 and 26.8 is provided. In a furtherembodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm M, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 8.982, 15.136, 20.738, 23.083 and 26.76 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm M which has an XRPD diffraction pattern substantially the same asFIG. 26 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm M which is characterized by XRPD diffraction peaks (2θ degrees±0.2)substantially the same as Table 26 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm M which is characterized by endotherms at about 124.2° C., 229.0°C., 246.0° C. and 256.0° C. and an exotherm at about 198.4° C. isprovided. In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm M which is characterized by endotherms at about 124.2° C. and246.0° C. and an exotherm at about 198.4° C. is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm M which is characterized by a DSC scan substantially the same asFIG. 54 is provided.

Certain embodiments provide a process for preparingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm M comprising:

(a) mixingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Ethanol and 1:1 THF:water; and

(b) recrystallizing the solid to prepare Form M.

Form N

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm N is provided. In certain embodiments, a substantially purecrystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm N is provided. Form N can be distinguished by the XRPD diffractionin FIG. 27 and/or peak assignments of the XRPD diffraction of FIG. 27 inTable 27.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm N, characterized by at least one specific XRPD diffraction peak atabout (2θ degrees±0.2) 22.9 is provided. In a further embodiment, acrystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm N, characterized by at least one specific XRPD diffraction peak atabout (2θ degrees±0.2) 22.92 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm N, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 15.9, 17.8, 19.2, 22.9 and 25.9 is provided. In a furtherembodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm N, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 15.88, 17.759, 19.202, 22.92 and 25.881 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm N, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 14.0, 15.9, 17.8, 18.1, 19.2, 22.9 and 25.9 is provided. Ina further embodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm N, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 14.02, 15.88, 17.759, 18.08, 19.202, 22.92 and 25.881 isprovided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm N which has an XRPD diffraction pattern substantially the same asFIG. 27 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm N which is characterized by XRPD diffraction peaks (2θ degrees±0.2)substantially the same as Table 27 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm N which is characterized by endotherms at about 111.0° C. and242.4° C. and an exotherm at about 146.1° C. is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm N which is characterized by a DSC scan substantially the same asFIG. 55 is provided.

Certain embodiments provide a process for preparingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm N comprising:

(a) mixingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Ethanol and a solution of 1% sodium carboxymethyl cellulose, 0.1%Tween® in water; and

(b) recrystallizing the solid to prepare Form N.

Form O

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm O is provided. In certain embodiments, a substantially purecrystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm O is provided. Form O can be distinguished by the XRPD diffractionin FIG. 28 and/or peak assignments of the XRPD diffraction of FIG. 28 inTable 28.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm O, characterized by at least one specific XRPD diffraction peak atabout (2θ degrees±0.2) 11.2 is provided. In a further embodiment, acrystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm O, characterized by at least one specific XRPD diffraction peak atabout (2θ degrees±0.2) 11.238 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm O, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 11.2, 16.5, 20.0, 22.2 and 25.6 is provided. In a furtherembodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm O, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 11.238, 16.52, 19.98, 22.179 and 25.638 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm O which has an XRPD diffraction pattern substantially the same asFIG. 28 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm O which is characterized by XRPD diffraction peaks (2θ degrees±0.2)substantially the same as Table 28 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm O which is characterized by an endotherm at about 245.4° C. isprovided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm O which is characterized by a DSC scan substantially the same asFIG. 56 is provided.

Certain embodiments provide a process for preparingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm O comprising:

(a) mixingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G hemi-Tetrahydrofuran with THF;

(b) creating a solution with theN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineand THF; and

(c) recrystallizing the solid to prepare Form O.

In certain embodiments, the solution in Step (b) is created by heatingthe mixture of Step (a) to about 50° C.

Form P

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm P is provided. In certain embodiments, a substantially purecrystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm P is provided. Form P can be distinguished by the XRPD diffractionin FIG. 29 and/or peak assignments of the XRPD diffraction of FIG. 29 inTable 29.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm P, characterized by at least one specific XRPD diffraction peak atabout (2θ degrees±0.2) 23.5 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm P, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 9.9, 13.7, 15.7, 17.7 and 23.5 is provided. In a furtherembodiment, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm P, characterized by XRPD diffraction peaks at about (2θdegrees±0.2) 9.901, 13.74, 15.662, 17.661 and 23.5 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm P which has an XRPD diffraction pattern substantially the same asFIG. 29 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm P which is characterized by XRPD diffraction peaks (2θ degrees±0.2)substantially the same as Table 29 is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm P which is characterized by endotherms at about 159.2° C., 246.7°C. and 262.2° C. is provided.

In certain embodiments, a crystalline polymorphN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm P which is characterized by a DSC scan substantially the same asFIG. 57 is provided.

Certain embodiments provide a process for preparingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm P comprising:

(a) mixingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G Tetrahydrofuran with water; and

(b) recrystallizing the solid to prepare Form P.

Amorphous

In certain embodiments, amorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineis provided. In certain embodiments, substantially pure amorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineis provided. AmorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineis identified in the XRPD of FIG. 30 .

In certain embodiments, amorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diaminewhich has an XRPD diffraction pattern substantially the same as FIG. 30is provided.

In certain embodiments, amorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diaminewhich is characterized by an mDSC scan substantially the same as FIG. 58is provided.

Certain embodiments provide a process for preparing amorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diaminecomprising:

(a) mixingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Ethanol with 3:7 water:THF;

(b) sonicating the solution of Step (a);

(c) freezing and lyophilizing the solution to prepare amorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.

The invention also includes isotopically-labeledN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine,which is identical, but for the fact that one or more atoms are replacedby an atom having an atomic mass or mass number different from theatomic mass or mass number usually found in nature. Examples of isotopesthat can be incorporated into compounds of the invention includeisotopes of hydrogen, carbon, nitrogen and oxygen, such as ²H, ³H, ¹³C,¹⁴C ¹⁵N, ¹⁸O and ¹⁷O, respectively. The polymorphs described herein,which contain the aforementioned isotopes and/or other isotopes of otheratoms are within the scope of this invention. Certainisotopically-labeled compounds of the present invention, for examplethose into which radioactive isotopes, such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³H and carbon-14, i.e., ¹⁴C, isotopes areparticularly widely used as a result of their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium, i.e., ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements and, hence, may be utilized insome particular circumstances. Isotopically labeled salts of the presentinvention can generally be prepared by carrying out procedures disclosedin WO 03/077914 by substituting a readily available isotopically labeledreagent for a non-isotopically labeled reagent during the preparation,or if desired, using an isotopically labeled sulfuric acid in thepreparation of the salt.

Synthesis of Compounds

Compounds described herein may be synthesized by synthetic routes thatinclude processes analogous to those well-known in the chemical arts,particularly in light of the description contained herein. The startingmaterials are generally available from commercial sources such asSigma-Aldrich (St. Louis, Mo.), Alfa Aesar (Ward Hill, Mass.), or TCI(Portland, Oreg.), or are readily prepared using methods well known tothose skilled in the art (e.g., prepared by methods generally describedin Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis. v.1-23, New York: Wiley 1967-2006 ed. (also available via the WileyInterScience® website), or Beilsteins Handbuch der organischen Chemie,4, Aufl. ed. Springer-Verlag, Berlin, including supplements (alsoavailable via the Beilstein online database)).

The synthesis ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineis described in WO 2007/059257. Generally,N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diaminemay be prepared by coupling(E)-N′-(2-cyano-4-(3-(1-hydroxy-2-methylpropan-2-yl)thioureido)phenyl)-N,N-dimethylformimidamidewith 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline inisopropyl acetate:acetic acid (65:35 v/v) at 45° C. to yield1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)-3-(1-hydroxy-2-methylpropan-2-yl)thiourea.The1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)-3-(1-hydroxy-2-methylpropan-2-yl)thioureamay then be agitated in tetrahydrofuran under basic conditions (2.5NNaOH), followed by the addition of p-toluenesulfonyl chloride. Water maythen be charged to yieldN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineas a mixture of polymorphs (generally a mixture containing one or moreof Form C, Form G hemi-THF, Form G mono-THF, Form M or Form P). Thefinal crystallizations or isolations will determine the polymorphicform, which are further detailed in the Examples section.

For a more detailed description of the individual reaction steps, seethe Examples section below. Those skilled in the art will appreciatethat other synthetic routes may be used to synthesize the compounds.

Administration and Pharmaceutical Formulations

The compounds described herein may be administered by any convenientroute appropriate to the condition to be treated. Suitable routesinclude oral, parenteral (including subcutaneous, intramuscular,intravenous, intraarterial, intradermal, intrathecal and epidural),transdermal, rectal, nasal, topical (including buccal and sublingual),ocular, vaginal, intraperitoneal, intrapulmonary and intranasal.

The compounds may be administered in any convenient administrative form,e.g., tablets, powders, capsules, solutions, dispersions, suspensions,syrups, sprays, suppositories, gels, emulsions, patches, etc. Suchcompositions may contain components conventional in pharmaceuticalpreparations, e.g., diluents, carriers, pH modifiers, sweeteners,bulking agents, and further active agents. If parenteral administrationis desired, the compositions will be sterile and in a solution orsuspension form suitable for injection or infusion.

A typical formulation is prepared by mixing a compound described hereinand a carrier or excipient. Suitable carriers and excipients are wellknown to those skilled in the art and are described in detail in, e.g.,Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and DrugDelivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004;Gennaro, Alfonso R., et al. Remington: The Science and Practice ofPharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe,Raymond C. Handbook of Pharmaceutical Excipients. Chicago,Pharmaceutical Press, 2005. The formulations may also include one ormore buffers, stabilizing agents, surfactants, wetting agents,lubricating agents, emulsifiers, suspending agents, preservatives,antioxidants, opaquing agents, glidants, processing aids, colorants,sweeteners, perfuming agents, flavoring agents, diluents and other knownadditives to provide an elegant presentation of the drug (i.e., acompound described herein or pharmaceutical composition thereof) or aidin the manufacturing of the pharmaceutical product (i.e., medicament).

One embodiment includes a pharmaceutical composition comprising apolymorph or amorphous compound described herein. A further embodimentprovides a pharmaceutical composition comprising a polymorph oramorphous compound described herein, together with a pharmaceuticallyacceptable carrier or excipient.

The amount of the active compound administered will be dependent on thesubject being treated, the severity of the disorder or condition, therate of administration, the disposition of the compound and thediscretion of the prescribing physician. However, an effective dosage isin the range of about 0.01 to about 100 mg per kg body weight per day,preferably about 1 to about 35 mg/kg/day, in single or divided doses.For a 70 kg human, this would amount to about 0.7 to 7000 mg/day,preferably about 70 to about 2500 mg/day. In some instances, dosagelevels below the lower limit of the aforesaid range may be more thanadequate, while in other cases still larger doses may be employedwithout causing any harmful side effect, provided that such larger dosesare first divided into several small doses for administration throughoutthe day. A unit dosage form such as a tablet or capsule will usuallycontain, for example 1-1000 mg of active ingredient, and preferably5-420 mg of active ingredient. Preferably a daily dose in the range of0.03-6 mg/kg is employed.

Methods of Treatment with Compounds of the Invention

Also provided are methods of treating or preventing disease or conditionby administering the pharmaceutical compositions described herein. Inone embodiment, a human patient is treated with a pharmaceuticalcomposition described herein in an amount to detectably inhibit ErbB2activity.

In another embodiment, a method of treating a hyperproliferative diseasein a mammal comprising administering a pharmaceutical compositiondescribed herein, to the mammal is provided.

In another embodiment, a method of treating or preventing cancer in amammal in need of such treatment, wherein the method comprisesadministering to said mammal a pharmaceutical composition describedherein. The cancer is selected from breast, ovary, cervix, prostate,testis, genitourinary tract, esophagus, larynx, glioblastoma,neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoidcarcinoma, large cell carcinoma, NSCLC, small cell carcinoma, lungadenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid,follicular carcinoma, undifferentiated carcinoma, papillary carcinoma,seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma andbiliary passages, kidney carcinoma, myeloid disorders, lymphoiddisorders, hairy cells, buccal cavity and pharynx (oral), lip, tongue,mouth, pharynx, small intestine, colon-rectum, large intestine, rectum,brain and central nervous system, Hodgkin's and leukemia. Anotherembodiment provides the use of a pharmaceutical composition describedherein, in the manufacture of a medicament for the treatment of cancer.

In another embodiment, the cancer is ErbB2 positive.

In another embodiment, the cancer is selected from breast, gastric,biliary, colorectal, brain, lung, NSCLC, pancreatic, head and neck,ovarian and uterine cancer.

In another embodiment, the cancer is selected from breast, gastric,biliary, colorectal, lung, NSCLC, pancreatic, head and neck, ovarian anduterine cancer.

In another embodiment, the cancer is selected from breast, gastric,colorectal, lung and ovarian cancer.

In another embodiment, the cancer is selected from breast, ovarian,gastric and uterine cancer.

In another embodiment, the cancer is selected from breast, gastric,colorectal, NSCLC and ovarian cancer.

In another embodiment, the cancer is selected from breast, lung,pancreatic, colorectal and head and neck cancers.

In another embodiment, the cancer is breast cancer.

In another embodiment, the cancer is gastric cancer.

In another embodiment, the cancer is biliary cancer.

In another embodiment, the cancer is colorectal.

In another embodiment, the cancer is lung cancer.

In another embodiment, the cancer is NSCLC.

In another embodiment, the cancer is pancreatic cancer.

In another embodiment, the cancer is head and neck cancer.

In another embodiment, the cancer is ovarian cancer.

In another embodiment, the cancer is uterine cancer.

In another embodiment, the cancer is brain cancer.

In another embodiment, a method of treating or preventing a disease ordisorder modulated by ErbB2, comprising administering to a mammal inneed of such treatment an effective amount of a pharmaceuticalcomposition described herein. Examples of such diseases and disordersinclude, but are not limited to, cancer.

Another embodiment provides a compound described herein in the treatmentof disease. In a further embodiment, the disease is a hyperproliferativedisease. In a further embodiment, the hyperproliferative disease iscancer.

Another embodiment provides the use of a pharmaceutical compositiondescribed herein, in the manufacture of a medicament for the treatmentof cancer.

Combination Therapy

The polymorphs and pharmaceutical compositions described herein may beemployed alone or in combination with other therapeutic agents fortreatment. The compounds described herein may be used in combinationwith one or more additional drugs, for example ananti-hyperproliferative (or anti-cancer) agent that works through actionon a different target protein. The second compound of the pharmaceuticalcombination formulation or dosing regimen preferably has complementaryactivities to the compound described herein, such that they do notadversely affect each other. Such molecules are suitably present incombination in amounts that are effective for the purpose intended. Thecompounds may be administered together in a unitary pharmaceuticalcomposition or separately and, when administered separately this mayoccur simultaneously or sequentially in any order. Such sequentialadministration may be close in time or remote in time.

EXAMPLES

For illustrative purposes, the following Examples are included. However,it is to be understood that these Examples do not limit the inventionand are only meant to suggest a method of practicing the invention.Persons skilled in the art will recognize that the chemical reactionsdescribed may be readily adapted to prepare the compounds or polymorphsdescribed herein, and alternative methods for preparing the compounds orpolymorphs are deemed to be within the scope of this invention. Forexample, the synthesis of the compounds or polymorphs may besuccessfully performed by modifications apparent to those skilled in theart, e.g., by appropriately protecting interfering groups, by utilizingother suitable reagents known in the art other than those described,and/or by making routine modifications of reaction conditions.Alternatively, other reactions disclosed herein or known in the art willbe recognized as having applicability for preparing the compounds orpolymorphs described herein. Persons skilled in the art will alsorecognize that the polymorphs and compositions described may be readilyadapted to prepare other polymorphs and compositions, and alternativemethods for preparing the polymorphs and compositions, as well asalternative compositions are deemed to be within the scope of thisinvention.

In the Examples described below, unless otherwise indicated alltemperatures are set forth in degrees Celsius. Reagents were purchasedfrom commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI, andwere used without further purification unless otherwise indicated. Thereactions set forth below were done generally under a positive pressureof nitrogen or argon or with a drying tube (unless otherwise stated) inanhydrous solvents, and the reaction flasks were typically fitted withrubber septa for the introduction of substrates and reagents viasyringe. Glassware was oven dried and/or heat dried.

The XRPD analysis was conducted using a Rigaku X-Ray powderdiffractometer (model Ultima III) operating with a Cu radiation sourceat 40 kW, 40 mA. Round standard aluminum sample holders with round zerobackground, and/or quartz plates were used for sample preparation. Thescanning parameters were from a range of about 3-40 degree 2θ (±0.2degrees) and a continuous scan at a rate of about 2 degrees 2θ/minute.2θ calibration was performed using a Si standard.

Peak assignment analysis was performed using Materials Data Inc. Jade 7(Version V5.1.2600) program, which uses a peak search algorithm that isbased on the Savitzky-Golay 2nd derivatives combined with the countingstatistics of intensity data. The peak search on each crystal form wasperformed using the following parameters: Parabolic Filter, PeakThreshold=3.0, Intensity Cutoff=0.1%, Background=3/1.0 and PeakLocation=Summit. The Tables below include the analysis and are providedwith the following approximate data: 2θ measured in degrees±0.2 degrees;d measured in angstroms±0.2 angstroms; and relative intensity using peakheight to measure height % (H %) in counts per second.

Thermal transition values were measured by differential scanningcalorimetry (“DSC”) using a TA Instruments Q1000 DSC on approximately2-10 mg samples in hermetically sealed aluminum pans with a pin-hole inthe lid under an inert nitrogen atmosphere. A heating rate of 10° C./minwas used over the 25-275° C. temperature range, and a second, emptyaluminum pan was used as a reference.

Glass transition values were measured by modulated differential scanningcalorimetry (“mDSC”) using a TA Instruments Q1000 DSC on approximately2-10 mg samples in hermetically sealed aluminum pans with a pin-hole inthe lid under an inert nitrogen atmosphere. A heating rate of 2° C./minwith a modulation amplitude of +/−1.3° C. over a period of 60 secondswas used. Samples were analyzed over a 25-150° C. temperature range, anda second, empty aluminum pan was used as a reference.

Example 1N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm A

AmorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine(20 mg) was added to a vial containing 1:1 EtOH:water (0.5 mL) andstirred for 48 hours at 50° C. The solution was cooled and filtered toyield Form A (Hydrate).

The XRPD scan is shown in FIG. 1 and the peak assignments are in Table1:

TABLE 1 Relative 2θ d (Å) Intensity 6.86 12.8745 34.5 9.158 9.6484 13.39.442 9.3588 18.5 9.723 9.0893 23.1 10.623 8.3213 29.6 10.943 8.078421.9 11.416 7.7451 13 12.78 6.921 49.4 13.637 6.4881 35.1 14.959 5.91756.7 15.219 5.8169 27.4 16.3 5.4336 48.8 16.94 5.2296 66.1 17.464 5.07427.1 17.92 4.946 11.9 18.139 4.8867 12.3 18.339 4.8338 13.7 18.745 4.737.8 19.138 4.6337 87.5 19.44 4.5624 36.3 20.278 4.3758 100 20.885 4.249922 21.16 4.1952 51.3 21.863 4.062 69.2 22.098 4.0194 16.5 22.604 3.93058.2 23.139 3.8408 78.8 23.98 3.708 32.7 24.519 3.6276 44.2 25.202 3.530872.1 25.901 3.4371 24.4 26.181 3.401 20.2 26.86 3.3166 13.2 27.2983.2643 31.9 27.733 3.2141 15.6 28.305 3.1504 7.4 28.864 3.0907 7.729.339 3.0417 16.6 29.66 3.0095 5.6 30.237 2.9534 5.3 30.642 2.9153 6.131.22 2.8626 11.9 32.042 2.791 5.7 32.459 2.7561 6.1 33.061 2.7073 15.933.318 2.687 4 33.802 2.6496 4.4 34.46 2.6005 8.9 35.679 2.5144 5.437.223 2.4136 3.8 38.178 2.3554 3.5 38.49 2.337 3.9

Example 2N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Methanol Isomorphic Solvate

N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E (666.5 mg) was added to a 20 mL scint vial, and MeOH was added(3.0 mL). The suspension was stirred with a magnetic stirrer at roomtemperature overnight. The suspension was filtered and washed with MeOH(2.0 mL). The solids were dried at 45° C. under vacuum for about 5 hoursand then dissolved at reflux in MeOH (50 mL). The solution was allowedto cool and placed in a refrigerator at about 5° C. for 5 days. Theresulting solids were collected by filtration after reducing the solventvolume using a rotovap to yield Form B Methanol.

The XRPD scan is shown in FIG. 2 and the peak assignments are in Table2:

TABLE 2 Relative 2θ d (Å) Intensity 6.881 12.836 6.9 8.46 10.4428 68.38.838 9.997 32.9 9.98 8.8555 100 10.297 8.5837 29.3 11.448 7.7236 10.112.917 6.8483 9.8 13.438 6.5839 72.7 14.124 6.2653 9.6 15.802 5.603739.5 16.243 5.4526 22.9 16.981 5.2171 60.7 17.4 5.0925 23.8 18.0424.9128 53 18.48 4.7971 25.6 19.72 4.4982 39.9 20.799 4.2672 53.5 21.1434.1987 37.6 21.622 4.1067 44.3 23.161 3.8371 49.4 23.579 3.7701 18.124.72 3.5986 59.5 25.519 3.4877 84.4 27.736 3.2137 6.2 28.278 3.1533 9.830.063 2.9701 20.2 32.469 2.7553 6.4 33.173 2.6984 7.6 33.926 2.6402 6.934.484 2.5988 7.9

Example 3N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Ethanol Isomorphic Solvate

Absolute ethanol (8.5 L) (10-16 mL/g) was added to a vial containing amixture ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diaminepolymorphs (553 g; prepared as described above in Synthesis of Compoundssection) and then heated to 70° C. The suspension was cooled to roomtemperature and agitated for over 12 hours. The suspension was filteredand washed twice with absolute ethanol (2×670 mL). The solids were driedin a vacuum oven at between 55° C. and 60° C. at 40 torr with a nitrogenbleed to yield Form B Ethanol (74.300 yield).

The XRPD scan is shown in FIG. 3 and the peak assignments are in Table3:

TABLE 3 Relative 2θ d (Å) Intensity 8.358 10.5709 20.9 8.752 10.095 4.69.859 8.9643 56.6 10.217 8.6507 7.9 10.748 8.2247 3.1 11.394 7.7598 5.513.3 6.6515 50 13.886 6.3722 5.1 15.642 5.6607 25.4 15.94 5.5555 6.516.862 5.2539 38.4 17.298 5.1224 19.2 17.94 4.9404 39.8 18.195 4.871826.1 18.384 4.822 12.7 19.342 4.5853 5.8 19.602 4.5252 38.8 20.7184.2838 51.5 34.102 2.627 5.8 35.006 2.5612 5.4 35.621 2.5184 5.1 37.32.4088 2.5 21.04 4.219 29.1 21.502 4.1293 46.3 22.402 3.9654 9 22.8013.897 8 23.08 3.8505 38.5 23.444 3.7915 15.1 24.019 3.702 3.5 24.2783.6631 4.3 24.621 3.6128 71.9 25.419 3.5013 100 25.785 3.4523 6 26.2023.3983 12.3 28.275 3.1537 5 28.978 3.0788 4.7 29.94 2.982 15.1 30.7642.904 4.8 31.196 2.8648 2.1 32.057 2.7897 4.2 32.959 2.7154 5.3 33.6352.6624 4.6 38.258 2.3506 7.6 38.935 2.3113 2.9 39.578 2.2752 4.3

Example 4N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Isopropyl Alcohol Isomorphic Solvate

IPA (50 mL) was added to a flask containingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm A (5.0 g) and was heated to reflux. Additional IPA (20 mL) wasadded and continued to heat at reflux. The solution was left stirringand allowed to cool to room temperature and then stored in arefrigerator overnight. The suspension was filtered and dried at roomtemperature to yield Form B Isopropyl Alcohol.

The XRPD scan is shown in FIG. 4 and the peak assignments are in Table4:

TABLE 4 Relative 2θ d (Å) Intensity 8.283 10.6656 41.6 8.661 10.2012 7.59.78 9.0365 95.7 10.273 8.6041 15.8 11.34 7.7963 11.1 13.201 6.7013 65.713.879 6.3757 8.2 15.498 5.7128 24.3 15.9 5.5694 6.1 16.88 5.2482 10017.24 5.1394 15.1 17.899 4.9515 88 18.378 4.8237 25.8 19.259 4.6049 34.519.542 4.5389 25.2 34.985 2.5627 6 35.618 2.5186 6.9 36.354 2.4693 5.520.6 4.3081 97.5 21.202 4.1872 48.1 21.48 4.1336 33.8 22.2 4.0011 7.822.981 3.8669 48 23.38 3.8017 10.8 24.198 3.675 45.9 24.582 3.6185 48.225.082 3.5475 67.8 25.362 3.5089 66.2 25.802 3.4501 7.3 26.239 3.39379.2 27.981 3.1862 4.9 29.879 2.988 21.5 31.884 2.8045 4.3 32.977 2.7148.3 34.024 2.6329 6.6 36.866 2.4361 3.9 38.082 2.3611 5.5

Example 5N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Acetonitrile Isomorphic Solvate

ACN (4 mL) was added to a 20 mL scint vial containingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E (647.9 mg), and the suspension was stirred magnetically at roomtemperature overnight. The suspension was filtered and washed with ACN(2 mL). The solids were dried at 45° C. under vacuum for about 5 hoursto yield Form B Acetonitrile.

The XRPD scan is shown in FIG. 5 and the peak assignments are in Table5:

TABLE 5 Relative 2θ d (Å) Intensity 8.46 10.4428 43.2 8.818 10.0203 15.39.98 8.8559 95.3 10.899 8.1114 8.3 13.46 6.5729 55.5 14.163 6.2484 9.615.82 5.5973 18.1 16.921 5.2357 56.3 17.442 5.0805 31.3 18.12 4.891646.4 18.438 4.808 28.4 19.426 4.5657 5.8 19.842 4.471 35 20.821 4.262930.4 21.239 4.1798 35.2 21.741 4.0844 50.1 22.64 3.9243 11.3 23.3193.8116 38.5 24.899 3.5731 61.5 25.661 3.4687 100 26.464 3.3653 18.728.283 3.1528 6.3 30.16 2.9607 16.6 31.946 2.7992 3.8 32.438 2.7579 4.833.042 2.7088 7.2 33.944 2.6389 9 34.539 2.5947 6.8

Example 6N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Acetone Isomorphic Solvate

Acetone (1 mL) was added to a 20 mL scint vial containing amorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine(113.0 mg), and the suspension was stirred with a magnetic stirrer atroom temperature for about 2 hours.N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E (503.5 mg) and acetone (2 mL) were added, and the suspension wasmagnetically stirred at room temperature overnight. The suspension wasfiltered and washed with acetone (2 mL). The solids were dried at 45° C.under vacuum for about 5 hours. The solids were slurried at reflux inacetone (100 mL), allowed to cool and stored in a refrigerator at about5° C. for over 5 days. The solvent was removed by rotovap, and thesolids were collected by filtration to yield Form B Acetone.

The XRPD scan is shown in FIG. 6 and the peak assignments are in Table6:

TABLE 6 Relative 2θ d (Å) Intensity 5.785 15.2648 7.3 8.378 10.5448 45.58.678 10.1814 11.3 9.936 8.8948 100 10.342 8.547 10.7 10.778 8.202 3.711.481 7.7015 15.6 13.041 6.7832 40.3 13.378 6.613 27.8 14.12 6.267 8.315.461 5.7265 12.4 16.119 5.4942 5.3 17.02 5.2052 70.8 17.98 4.9295 49.918.478 4.7977 27.5 33.016 2.7109 3.9 19.068 4.6506 3.9 19.758 4.489737.6 20.302 4.3706 31.7 20.759 4.2754 27.2 21.041 4.2188 33 21.8214.0698 32.2 22.481 3.9518 18 23.14 3.8406 18.6 23.498 3.783 35.8 24.6793.6045 60.2 25.52 3.4875 85.2 26.312 3.3843 5 26.641 3.3434 6.1 28.1193.1709 7.7 28.985 3.0781 3.8 30.061 2.9703 15.2 32.099 2.7862 4 33.7572.653 3.9

Example 7N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Dichloromethane Isomorphic Solvate

DCM (1 mL) was added to a 20 mL scint vial containing amorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine(181.7 mg), and the suspension was stirred with a magnetic stirrer atroom temperature for about 2 hours.N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E (506.3 mg) and DCM (2 mL) were added, and the suspension wasmagnetically stirred at room temperature overnight. The suspension wasfiltered and washed with DCM (2 mL). The solids were dried at 45° C.under vacuum for about 5 hours. The solids were slurried at reflux inDCM (5 mL), allowed to cool and stored in a refrigerator at about 5° C.for over 5 days. The solids were collected by filtration to yield Form BDichloromethane.

The XRPD scan is shown in FIG. 7 and the peak assignments are in Table7:

TABLE 7 Relative 2θ d (Å) Intensity 7.96 11.0985 28 8.439 10.4697 55.98.817 10.0216 12.6 9.517 9.2861 19 9.977 8.8582 84.5 10.265 8.6109 29.311.47 7.7085 18.5 12.579 7.0311 21.8 13.381 6.6116 88.6 15.796 5.605932.4 16.918 5.2364 100 17.438 5.0814 37.3 18.041 4.9128 57.4 18.344.8335 45.8 19.336 4.5867 18.1 19.899 4.4582 48 20.738 4.2797 81.921.161 4.1951 38.9 21.802 4.0732 44.8 23.46 3.789 48.8 24.779 3.590272.2 25.641 3.4715 75.3 26.441 3.3681 16.4 28.27 3.1543 16.5 30.3192.9456 16.3 34.536 2.5949 11.3

Example 8N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Tetrahydrofuran Isomorphic Solvate

THF (4 mL) was added to a vial containingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G mono-Tetrahydrofuran (300 mg), and the contents were agitated atroom temperature. The contents were filtered and washed with THF (3×0.8mL). The solids were dried in a vacuum oven at 45° C. with a nitrogenbleed to yield Form B Tetrahydrofuran (91.8% yield).

The XRPD scan is shown in FIG. 8 and the peak assignments are in Table8:

TABLE 8 Relative 2θ d (Å) Intensity 8.262 10.6932 33 8.679 10.1799 15.59.819 9.0002 84.9 10.718 8.2473 7.1 13.38 6.6123 61.1 13.96 6.3388 12.515.72 5.6327 22.4 16.7 5.3042 65.3 17.179 5.1575 26.2 17.92 4.9459 70.919.541 4.5392 30.8 20.58 4.3121 21.6 21.4 4.1489 58.7 22.92 3.877 40.724.66 3.6072 64 25.44 3.4984 100 26.079 3.414 20.6 28.28 3.1532 4.129.84 2.9918 13.8 32.237 2.7746 3.9 32.781 2.7298 5.2 33.7 2.6574 7.735.262 2.5432 7.2 37.296 2.4091 2.6 38.335 2.3461 3.8 39.4 2.2851 2.2

Example 9N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Anhydrous

N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Ethanol (1.10 g) was placed in a watch glass, which was thenplaced in an oven at 100° C. with nitrogen flowing through it. The solidwas removed after 5 days and placed in a 25 mL round bottom flask andheated to 200° C. under high vacuum for 1 hour. The sample was againplaced in the oven at 200° C. under high vacuum for 3 hours. The solidswere collected in a 20 mL scint vial to yield Form B Anhydrous.

The XRPD scan is shown in FIG. 9 and the peak assignments are in Table9:

TABLE 9 Relative 2θ d (Å) Intensity 8.44 10.4679 37.8 8.855 9.9777 18.79.938 8.8932 100 10.902 8.1086 9 12.642 6.9962 2.4 13.641 6.4863 54.214.28 6.1975 12.4 16.016 5.5294 25.5 16.841 5.2602 43.8 17.099 5.181337.1 17.439 5.0813 27 18.1 4.8971 54.1 18.42 4.8127 22.9 19.697 4.503525.8 20.222 4.3877 5.8 20.704 4.2867 11.1 21.22 4.1835 42.8 21.4984.1301 45.6 22.56 3.9381 4.1 23 3.8636 24.7 23.538 3.7766 14.6 24.9013.5729 35.1 25.541 3.4848 60.4 26.159 3.4038 13.6 28.078 3.1754 1.728.558 3.1231 2.9 29.213 3.0545 2.4 29.879 2.9879 9.4 30.242 2.9529 3.531.379 2.8485 2.6 31.845 2.8079 2.3 32.416 2.7597 2.9 32.944 2.7166 3.333.943 2.6389 4.1 34.657 2.5862 1.7 35.463 2.5292 5.5 37.385 2.4035 1.938.582 2.3316 2.7 39.558 2.2764 1.3

Example 10N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm C

2-Methoxyethanol (200 mL) was added to a 500 mL Erlenmeyer flaskcontainingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm A (15.11 g), and the solution was heated to 50° C. with stirring.The flask was cooled to room temperature, and the volume was reduced toabout 50 mL by rotovap. The flask was allowed to stand for 2 hours. EtOH(200 mL) was added, and the contents of the flask were stirred, filteredand washed with EtOH (3×15 mL). The solid was dried at 50° C. undervacuum overnight to yield Form C (Anhydrous).

The XRPD scan is shown in FIG. 10 and the peak assignments are in Table10:

TABLE 10 Relative 2θ d (Å) Intensity 5.04 17.52 100 7.159 12.3378 69.610.159 8.7004 68.2 11.376 7.772 16.2 11.902 7.4299 29.8 12.16 7.2724 9.212.977 6.8163 17.9 14.435 6.1313 76.8 15.301 5.786 99.8 15.717 5.633866.7 16.121 5.4936 29.8 16.719 5.2985 43.3 17.501 5.0632 76.3 18.0594.908 36.8 18.437 4.8084 88.4 18.902 4.6911 90.7 19.638 4.5168 74.120.479 4.3333 30.7 21.08 4.2111 42.2 21.437 4.1418 42.3 21.74 4.084827.8 22.34 3.9763 52.8 22.878 3.884 24.6 23.779 3.7389 32 24.181 3.677664.8 24.58 3.6188 33.1 25.262 3.5226 11 25.679 3.4663 11 26.096 3.411929.8 26.809 3.3228 5.8 27.18 3.2783 19.1 27.675 3.2208 8.4 27.88 3.19758.6 28.417 3.1383 16 28.599 3.1187 16.3 30.021 2.9742 7.6 31.113 2.87225.5 31.863 2.8063 6.6 32.674 2.7385 5.9 33.339 2.6853 17.7 34.234 2.61716 34.878 2.5703 8.6 37.442 2.4 8.9

Example 11N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Ethyl Acetate Isomorphic Solvate

EtOAc (2.0 mL) was added to a 4 mL vial containing amorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine(394 mg), and the contents were stirred overnight at room temperature.The solids were dried under a stream of nitrogen to yield Form D EthylAcetate.

The XRPD scan is shown in FIG. 11 and the peak assignments are in Table11:

TABLE 11 Relative 2θ d (Å) Intensity 5.596 15.7789 13.5 6.741 13.1015 117.959 11.0998 100 9.139 9.669 3.4 9.798 9.0196 38.7 11.321 7.8099 35.512.66 6.9863 61.3 13.917 6.3581 33.9 16.099 5.501 54.8 17.118 5.175748.3 18.017 4.9194 33.9 18.937 4.6825 6.4 19.761 4.489 47.4 21.3794.1529 28.2 22.139 4.012 23.9 22.557 3.9386 7.6 22.93 3.8753 5.9 23.5993.7669 38.3 24.241 3.6686 18.7 25.34 3.512 13.7 25.66 3.4689 15.5 27.523.2385 33.6 28.142 3.1684 5.4 28.724 3.1054 4.6 29.023 3.0742 4.7 29.3593.0397 4.4 30.045 2.9719 2.7 31.56 2.8326 4.8 32.093 2.7867 3.8 32.7012.7363 2.7 33.243 2.6929 3.5 37.161 2.4175 2.7

Example 12N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Dioxane Isomorphic Solvate

Dioxane (600 μL) was added to a vial containing amorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine(90 mg), and the contents were allowed to stir overnight. The solidswere filtered and dried at room temperature to yield Form D Dioxane.

The XRPD scan is shown in FIG. 12 and the peak assignments are in Table12:

TABLE 12 Relative 2θ d (Å) Intensity 7.822 11.294 99.1 9.34 9.4615 30.39.759 9.0562 33.4 11.139 7.9369 98.7 12.5 7.0753 86.2 13.378 6.6132 16.113.763 6.429 32.4 15.841 5.5899 17 16.461 5.3808 32.6 17.135 5.1708 43.317.703 5.0059 35 19.54 4.5394 100 21.062 4.2146 84.1 21.901 4.0551 2823.139 3.8409 89.2 24.022 3.7016 53 25.202 3.5309 33.4 27.179 3.278462.6 28.859 3.0912 18.6 37.578 2.3916 9.4 39.493 2.2799 9.1

Example 13N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Acetone Isomorphic Solvate

Acetone (300 μL) was added to a vial containingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E (100 mg), and the contents were allowed to stir overnight. Thesolids were filtered and dried at room temperature to yield Form DAcetone.

The XRPD scan is shown in FIG. 13 and the peak assignments are in Table13:

TABLE 13 Relative 2θ d (Å) Intensity 5.656 15.6134 10.8 7.999 11.0445100 8.603 10.2695 2.9 9.856 8.9671 43.6 11.359 7.7837 33.7 12.681 6.974848.3 13.923 6.3555 55.6 16.101 5.5003 59.5 17.14 5.169 83.3 17.6255.0278 6.4 18 4.9241 36.7 18.941 4.6815 13.8 19.761 4.489 56.4 20.5814.3121 7.2 21.378 4.153 63 22.103 4.0185 38.1 22.541 3.9413 13.9 22.93.8804 16 23.561 3.7729 71.5 24.259 3.6659 42.6 25.063 3.5501 5.8 25.3393.5121 21.6 25.622 3.474 29.3 26.981 3.3019 11.2 27.482 3.2429 82.128.122 3.1705 15.5 28.723 3.1056 13.1 29.002 3.0763 10.1 29.339 3.041711.7 29.848 2.991 4.3 30.2 2.9569 4.1 31 2.8824 3.8 31.539 2.8344 5.132.041 2.7911 10.8 32.662 2.7395 9.3 33.218 2.6949 7.6 33.611 2.6642 3.635.201 2.5474 4.1 35.675 2.5147 3.1 37.117 2.4203 8 39.058 2.3043 6

Example 14N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm D Propyl Acetate Isomorphic Solvate

Propyl acetate (400 μL) was added to a vial containingN4-(4-[1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E (50 mg), and the contents were allowed to stir overnight. Thesolids were filtered and dried at room temperature to yield Form DPropyl Acetate.

The XRPD scan is shown in FIG. 14 and the peak assignments are in Table14:

TABLE 14 Relative 2θ d (Å) Intensity 5.074 17.4026 6.3 5.623 15.7043 8.47.189 12.2862 5.2 7.999 11.0438 100 9.839 8.9821 43.1 10.158 8.7009 7.511.362 7.7816 32.3 12.719 6.9541 68.2 13.903 6.3648 39.7 14.381 6.15396.4 15.701 5.6395 10.3 16.121 5.4937 68.2 17.16 5.1633 84.4 17.5745.0423 8.5 18.021 4.9183 38.5 18.419 4.813 9.8 18.96 4.677 19.2 19.7824.4844 68.7 20.65 4.2977 7.7 21.42 4.1449 38.6 22.201 4.0008 33.5 22.5963.9318 16.5 22.92 3.8771 15.1 23.62 3.7637 61.7 24.28 3.6629 45.7 25.3793.5066 26.7 25.681 3.466 26.4 27.579 3.2317 54.1 28.825 3.0948 9.129.137 3.0623 10.8 29.365 3.0391 6.1 31.503 2.8376 8.4 32.019 2.793 5.232.699 2.7364 6 33.283 2.6898 7.8 37.179 2.4164 4.6 39.104 2.3017 5

Example 15N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E

N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diaminewas synthesized from1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)-3-(1-hydroxy-2-methylpropan-2-yl)thiourea(322 g) in THF (3 L) at 0° C. Water (10 L) was added, and the solutionwas allowed to stir for 1 hour, at which point the material oiled out.The organics were then extracted into ethyl acetate (3×5000 mL),combined and washed with water (2×5000 mL) and brine (2×5000 mL). Theorganics were dried by rotoevaporation, and the material wasconcentrated to an oil. The oil was observed to solidify at roomtemperature to yield Form E.

The XRPD scan is shown in FIG. 15 and the peak assignments are in Table15:

TABLE 15 Relative 2θ d (Å) Intensity 8.659 10.204 44.5 9.353 9.4482 38.410 8.8382 4.8 11.904 7.4284 27.3 12.416 7.123 14.8 12.923 6.8451 19.315.36 5.7638 11 16.06 5.5143 100 16.338 5.421 16.6 16.709 5.3015 2.916.918 5.2363 8 17.457 5.0759 4.9 18.03 4.9158 3.8 18.4 4.8179 8.119.021 4.6621 11.2 19.619 4.5212 19.4 20.08 4.4186 23.4 20.656 4.29653.8 21.296 4.1689 18.1 21.62 4.107 12.6 22.179 4.0047 1.8 22.821 3.893518.4 23.739 3.745 43.6 24.358 3.6512 6.7 24.94 3.5674 2.7 25.295 3.518 325.459 3.4958 2.5 26.106 3.4107 3.5 27.035 3.2955 3.6 27.8 3.2065 6.828.297 3.1513 15.4 29.237 3.0521 2.3 30.716 2.9084 2.7 31.799 2.8118 4.932.507 2.7522 1.7 36.658 2.4495 1.9 39.055 2.3045 1.5

Example 16N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm F

Ethyl acetate (5 mL) was added to a vial containingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E (1 g), and the contents were stirred for 48 hours. The solid wasfiltered and dried overnight in a vacuum oven at room temperature toyield Form F (Ethyl Acetate solvate).

The XRPD scan is shown in FIG. 16 and the peak assignments are in Table16:

TABLE 16 Relative 2θ d (Å) Intensity 6.981 12.6512 8.2 7.58 11.6541 158.24 10.7212 14.5 9.483 9.3191 12.6 11.04 8.008 4.5 11.498 7.6901 32.512.321 7.178 9.5 12.859 6.8787 12.4 13.633 6.49 2.5 13.897 6.3675 2.714.899 5.9413 41.3 15.906 5.5673 4.1 16.56 5.3487 100 16.92 5.2357 50.218.502 4.7916 14.9 19.098 4.6433 87.8 19.62 4.5209 32.4 20.663 4.295212.9 21.18 4.1914 35.4 21.633 4.1046 8 22.24 3.994 22.1 22.537 3.94235.1 23.004 3.8631 16.3 23.361 3.8047 9.3 23.996 3.7056 24.8 24.4233.6417 6.6 24.942 3.567 26 25.379 3.5067 13.8 26.418 3.371 6.7 26.7383.3314 4.4 27.34 3.2594 25.3 27.913 3.1938 4.3 28.38 3.1423 5.4 29.023.0744 15.7 29.915 2.9844 4.6 31.941 2.7996 4.5 33.417 2.6793 4.5 35.2012.5475 4.8 36.042 2.4899 2.8

Example 17N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G hemi-Tetrahydrofuran Isomorphic Solvate

THF:water (2 mL, 20:80) was added to a vial containingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G mono-Tetrahydrofuran (100 mg), and the contents were stirred atroom temperature overnight. The contents were then heated to 40° C. andstirred overnight. The solids were filtered and collected to yield FormG hemi-Tetrahydrofuran.

The XRPD scan is shown in FIG. 17 and the peak assignments are in Table17:

TABLE 17 Relative 2θ d (Å) Intensity 5.148 17.1528 3.5 5.521 15.995 13.17.719 11.4438 91.4 8.018 11.0172 28.3 9.379 9.4216 28.6 11.102 7.96342.1 12.281 7.201 49.9 12.737 6.9445 17.6 13.263 6.67 13.8 13.897 6.36733.3 14.097 6.2772 5.9 15.558 5.6909 20.2 16.142 5.4863 16.5 16.5445.3541 32.6 16.955 5.2253 10.4 17.26 5.1336 16.1 17.519 5.0583 17.418.096 4.8982 16.6 29.062 3.07 6.3 29.814 2.9943 9 18.837 4.7072 15.619.26 4.6047 16.8 19.72 4.4982 19.6 20.26 4.3795 22.6 20.645 4.2989 5.321.022 4.2225 30.3 21.243 4.1792 22.2 21.865 4.0617 7.5 22.6 3.9311 9.223.079 3.8507 100 23.359 3.8052 34.1 24.099 3.69 55.8 24.48 3.6333 11.524.934 3.5683 6.3 25.222 3.5281 10.7 26.839 3.3191 17.6 27.282 3.266216.1 27.503 3.2404 37.7 28.281 3.1531 6.7 28.52 3.1272 7.7 31.297 2.85584.3 32.39 2.7619 5.4

Example 18N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G mono-Tetrahydrofuran Isomorphic Solvate

THF (150 mL) was added to a flask containingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm A (5.17 g), and the contents were heated to reflux until all of thesolids dissolved. The heat was removed, and the flask was allowed tocool to room temperature with stirring overnight. The volume was reducedto about 50 mL by nitrogen evaporation. The flask was stored in arefrigerator overnight. The contents of the flask were filtered andwashed with THF (2×10 mL). The solids were dried at 50° C. under vacuumovernight to yield Form G mono-Tetrahydrofuran.

The XRPD scan is shown in FIG. 18 and the peak assignments are in Table18:

TABLE 18 Relative 2θ d (Å) Intensity 5.522 15.9921 20.2 7.72 11.443287.8 8.003 11.039 45.6 9.417 9.3841 39.8 11.137 7.9379 60.5 12.4017.1321 58.8 12.734 6.946 24.7 13.281 6.6612 16.6 13.825 6.4002 4.914.083 6.2837 9.5 15.559 5.6908 19.6 16.159 5.4806 19.6 16.599 5.336544.8 25.222 3.5281 9.6 26.82 3.3214 23.9 27.482 3.2429 38.2 28.4633.1333 10.5 16.961 5.2233 18.7 17.318 5.1164 27.2 17.54 5.0521 18.318.14 4.8864 22.5 18.858 4.702 19.9 19.3 4.5952 17.8 19.739 4.4939 27.120.257 4.3802 21.8 21.017 4.2235 40.5 21.24 4.1796 29.3 22.601 3.930912.2 23.022 3.8601 100 23.397 3.799 38.6 24.042 3.6985 77.4 24.4193.6423 11.8 29.06 3.0703 8.2 29.8 2.9957 8.5 30.664 2.9132 5.6 32.3822.7625 7

Example 19N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G Isopropyl Acetate Isomorphic Solvate

Isopropyl acetate (5 mL) was added to a vial containingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E (500 mg), and the contents were stirred at room temperature for48 hours. The contents were filtered and dried overnight in a vacuumoven at room temperature to yield Form G Isopropyl Acetate.

The XRPD scan is shown in FIG. 19 and the peak assignments are in Table19:

TABLE 19 Relative 2θ d (Å) Intensity 5.601 15.765 18.2 7.803 11.321561.8 8.299 10.6452 55.3 9.361 9.4403 52.3 9.841 8.9804 11.8 11.3987.7568 59.8 12.7 6.9646 49.6 13.18 6.712 52.7 14.026 6.3092 5 15.9615.5483 34.8 16.64 5.3232 52.6 17.121 5.1748 28.6 17.457 5.076 10.618.099 4.8973 36.6 18.655 4.7526 22.1 31.641 2.8255 8.5 32.799 2.72835.4 19.04 4.6573 17.9 19.639 4.5166 38.4 19.979 4.4405 49.1 20.58 4.312226.8 21.323 4.1636 17.8 21.738 4.0851 46.5 22.58 3.9345 27.7 23.4383.7924 100 23.739 3.745 32.1 24.381 3.6478 51.6 24.737 3.5961 34.425.084 3.5472 12.2 26.605 3.3478 10.1 27.821 3.2042 46.9 29.303 3.04546.8 29.899 2.986 14.5 31.171 2.867 5.3 33.295 2.6888 6 38.788 2.3197 6.4

Example 20N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G Methyl Isobutyl Ketone Isomorphic Solvate

MIBK (400 μL) was added to a vial containingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E (50 mg), and the suspension was stirred at room temperatureovernight. The solids were filtered and dried to yield Form G MethylIsobutyl Ketone.

The XRPD scan is shown in FIG. 20 and the peak assignments are in Table20:

TABLE 20 Relative 2θ d (Å) Intensity 4.824 18.302 12.3 5.638 15.661626.6 7.78 11.3544 95.5 8.217 10.7513 58.1 9.298 9.5039 50.4 11.2397.8665 72.1 11.515 7.6787 13.8 12.341 7.1661 46.1 12.575 7.0334 46.913.079 6.7636 50.2 13.437 6.5842 19 14.338 6.1723 16.4 15.715 5.634616.1 16.221 5.4599 29.8 16.503 5.3672 69.4 16.993 5.2135 28.4 17.4155.0881 25.4 29.898 2.9862 17.4 31.866 2.806 14.3 17.961 4.9347 29.218.503 4.7914 32.5 19.036 4.6585 24.8 19.35 4.5835 21.3 19.66 4.512 22.719.858 4.4674 52 20.52 4.3247 24 21.221 4.1834 27.4 21.442 4.1408 5021.641 4.1032 28.3 22.305 3.9825 25.8 22.644 3.9236 16.1 23.28 3.8178100 23.619 3.7637 46.7 24.562 3.6214 56.6 24.997 3.5593 23.7 27.4773.2435 27.1 27.759 3.2111 50.5 28.302 3.1508 23.6 33.135 2.7014 10.4

Example 21N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm H

MTBE (600 μL) was added to a vial containing amorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine(90 mg), and the contents were stirred at room temperature overnight.The solids were filtered and dried at room temperature to yield Form H(Methyl tert-Butyl Ether solvate).

The XRPD scan is shown in FIG. 21 and the peak assignments are in Table21:

TABLE 21 Relative 2θ d (Å) Intensity 7.38 11.9685 14.9 9.246 9.5576 11.111.18 7.908 100 12.701 6.9638 12.2 16.08 5.5075 55.8 18.696 4.7422 9.919.58 4.5302 30.1 22.04 4.0298 73.9 24.741 3.5955 21.7 25.501 3.490129.6 26.738 3.3314 13.3 27.86 3.1997 11.7 28.198 3.1621 7.5 31.901 2.8037.3 33.618 2.6637 7.8

Example 22N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm I

Xylene (600 μL) was added to a vial containing amorphousN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine(90 mg), and the contents were stirred at room temperature overnight.The solids were filtered and dried at room temperature to yield Form I(Xylenes solvate).

The XRPD scan is shown in FIG. 22 and the peak assignments are in Table22:

TABLE 22 Relative 2θ d (Å) Intensity 4.318 20.4483 11.8 7.2 12.268 1008.065 10.9535 33.7 8.421 10.4921 19.4 9.603 9.2023 8.9 10.343 8.545934.1 11.101 7.9636 33.8 12.117 7.2984 37.7 12.664 6.9844 20.2 13.0576.7751 17.4 14.961 5.9169 22.7 15.222 5.816 28.1 16.319 5.4272 35.316.559 5.3491 64.2 16.798 5.2735 27.6 17.578 5.0414 19.1 18.303 4.843459.5 18.904 4.6907 24.3 19.32 4.5905 39.8 19.54 4.5394 39.6 20.2614.3794 33.3 20.641 4.2997 35.9 21.082 4.2107 27.8 22.282 3.9866 40.323.101 3.8471 44 23.942 3.7137 21.6 25.134 3.5403 7.6 25.541 3.4847 20.726.341 3.3807 27.7 27.198 3.2761 9.2 27.395 3.2529 9.6 27.667 3.2216 7.429.58 3.0174 9.7

Example 23N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm J

2-Methoxyethanol (4 mL) was added to a 20 mL scint vial containingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E (1013.25 mg), and the contents were stirred at room temperaturefor about 6 hours. The contents were filtered and washed with2-methoxyethanol (2×10 mL). The solids were dried on the filter at roomtemperature for about 1 hour to yield Form J (2-Methoxyethanol solvate).

The XRPD scan is shown in FIG. 23 and the peak assignments are in Table23:

TABLE 23 Relative 2θ d (Å) Intensity 4.019 21.9675 4.5 4.479 19.713453.2 6.777 13.0322 25.4 8.982 9.838 49.8 10.358 8.5335 3.2 11.874 7.44692.4 12.083 7.319 4.5 12.724 6.9517 18.9 13.521 6.5434 29.6 14.463 6.11924.7 15.014 5.896 6.2 16.963 5.2228 100 18.078 4.903 88.2 18.797 4.716939.4 19.317 4.5912 11.4 19.858 4.4673 32.5 20.156 4.4019 25.4 20.8384.2595 23.3 21.761 4.0808 31.2 22.118 4.0158 9.4 22.682 3.9171 12.923.298 3.8149 19 24.062 3.6955 15.2 24.658 3.6076 16.7 24.957 3.564916.9 25.664 3.4683 21.4 26.167 3.4028 6.4 26.734 3.3319 6 26.998 3.29994.1 27.299 3.2642 16.3 27.497 3.2411 9.8 27.638 3.2249 6.9 28.779 3.09962.7 30.02 2.9742 4.9 31.106 2.8729 3.1 32.043 2.791 10.5 33.279 2.69 4.533.604 2.6648 4.6 34.407 2.6044 4.4 35.097 2.5548 3.2 36.444 2.4634 4.436.655 2.4497 2.8 37.891 2.3726 2.2 38.179 2.3553 2.9 38.459 2.3388 2.339.413 2.2844 2.2

Example 24N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm K

DME (4 mL) was added to a 20 mL scint vial containingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E (939.4 mg), and the contents were stirred at room temperature forabout 6 hours. The contents were filtered and washed with DME (2×10 mL).The solids were dried at 50° C. under vacuum overnight to yield Form K(Dimethoxyethane solvate).

The XRPD scan is shown in FIG. 24 and the peak assignments are in Table24:

TABLE 24 Relative 2θ d (Å) Intensity 6.923 12.7574 32.9 8.499 10.39568.4 10.137 8.7186 3.2 11.036 8.011 12.5 11.836 7.4712 28.8 12.054 7.33634.3 12.743 6.9411 10.2 13.259 6.6723 5.8 13.923 6.3553 38.8 14.7755.9908 10.3 15.797 5.6056 62.7 16.96 5.2237 20.8 17.16 5.1632 31.8 17.625.0293 58.8 17.998 4.9246 34.6 18.482 4.7967 3.2 18.683 4.7455 8 18.9994.6673 39.5 21.041 4.2187 4.9 21.24 4.1797 9.2 21.796 4.0744 4.8 21.8984.0555 4.7 22.177 4.0051 4.5 22.78 3.9005 100 23 3.8638 77.9 23.3363.8088 3.8 23.863 3.7259 3.6 24.205 3.674 7.1 24.503 3.63 8.2 25.2693.5217 4.2 25.701 3.4635 42.8 27.101 3.2876 27.3 28.26 3.1554 6 28.8213.0952 5.8 29.258 3.0499 4.2 29.441 3.0314 6.6 29.864 2.9894 4.5 30.4442.9338 5.6 30.749 2.9054 2.5 31.942 2.7995 5.5 32.94 2.7169 2.8 33.8642.6449 4.3 35.505 2.5264 2.3 36.018 2.4915 3.3 37.375 2.4041 2.3 38.2452.3514 2.3 38.876 2.3147 2.4 39.333 2.2888 2.4

Example 25N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm L

MeOAc (400 μL) was added to a vial containingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm E (50 mg), and the contents were stirred overnight at roomtemperature. The solids were filtered and dried to yield Form L (MethylAcetate solvate).

The XRPD scan is shown in FIG. 25 and the peak assignments are in Table25:

TABLE 25 Relative 2θ d (Å) Intensity 5.028 17.5604 5.3 6.978 12.657 10.47.602 11.6193 13.4 8.301 10.6435 15.1 9.34 9.4614 5.5 9.638 9.1691 3.511.523 7.673 22.9 12.281 7.2015 3.5 12.758 6.9332 20.1 14.899 5.941464.5 15.463 5.7257 10.4 16.198 5.4675 12.2 16.98 5.2176 100 17.5215.0575 9.1 18.478 4.7978 12.7 18.958 4.6773 89.8 19.62 4.5211 27.220.822 4.2627 16.4 21.062 4.2147 37.3 21.462 4.137 20.3 22.122 4.015 9.222.457 3.9558 47.9 23.019 3.8606 15.7 23.661 3.7572 7.4 24.126 3.68597.3 24.6 3.6159 16.9 25.7 3.4636 16.9 26.311 3.3845 7.2 27.183 3.277917.1 27.819 3.2044 11.7 28.64 3.1144 12.5 29.736 3.002 6.2 30.939 2.8885.1 31.197 2.8647 4.3 32.037 2.7915 5.7 32.379 2.7627 6.1 32.742 2.73294.9 33.764 2.6525 4.5 35.919 2.4981 3.8 38.746 2.3222 3.3

Example 26N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm M

THF:water (0.4 mL, 1:1) was added to a flask containingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Ethanol (50 mg), and the contents were stirred for 24 hours atroom temperature. The solids were filtered and dried at room temperatureto yield Form M (Tetrahydrofuran:Water solvate) (86% yield).

The XRPD scan is shown in FIG. 26 and the peak assignments are in Table26:

TABLE 26 Relative 2θ d (Å) Intensity 8.982 9.8379 100 10.375 8.5192 24.711.194 7.8982 4.2 13.379 6.6124 13.3 14.422 6.1366 7.7 15.136 5.848734.5 15.561 5.6899 26.3 16.057 5.5153 8.5 16.255 5.4484 10.3 17.0095.2086 3.6 17.383 5.0975 3.7 17.859 4.9625 7.4 18.201 4.8702 23.4 18.544.7819 7.5 18.819 4.7115 7.8 20.738 4.2798 47.8 21.395 4.1497 21.822.583 3.9341 15.8 23.083 3.8501 68.1 23.455 3.7897 13.6 23.863 3.72593.6 24.419 3.6422 4.4 24.715 3.5993 4.2 24.943 3.5669 4.9 25.438 3.49873.3 25.822 3.4474 3.8 26.44 3.3683 5.2 26.76 3.3287 29.9 27.301 3.26396.8 28.126 3.17 2.9 29.178 3.0581 6 29.459 3.0296 13.8 30.543 2.9245 8.532.507 2.7522 3.1 34.461 2.6005 3.3

Example 27N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm N

A solution of 1% NaCMC and 0.1% Tween® in water (2 mL) was added to avial containingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Ethanol (51.26 mg). The vial was placed on a stir plate andallowed to stir for 2 weeks at room temperature. Solids were collectedby filtration and washed with water (2×3 mL). The solids were collectedand dried under vacuum at room temperature overnight to yield Form N(Hydrate).

The XRPD scan is shown in FIG. 27 and the peak assignments are in Table27:

TABLE 27 Relative 2θ d (Å) Intensity 7.04 12.5463 33.6 8.142 10.8505 9.28.521 10.3682 15.6 8.902 9.9256 6.9 10.238 8.6335 8.5 11.16 7.9217 14.511.941 7.4055 29 12.918 6.8476 9.5 13.36 6.6221 7.4 14.02 6.3115 36.914.903 5.9398 9.6 15.88 5.5764 66.7 17.378 5.0988 32.6 17.759 4.990353.9 18.08 4.9025 35.3 19.202 4.6185 40.1 21.302 4.1676 11.2 21.8954.0561 3.6 22.92 3.877 100 24.074 3.6937 4.8 24.701 3.6013 10.9 25.8813.4398 41.7 27.319 3.2618 29.9 28.401 3.14 8.5 28.999 3.0766 5.5 29.5393.0216 6 30.041 2.9722 4.9 30.578 2.9213 5.8 32.138 2.7829 5 33.0812.7057 5.1 34.001 2.6346 4.7 35.623 2.5183 3.8 36.195 2.4797 4.8 37.2912.4093 2.3

Example 28N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm O

THF (40 g) was added to a vial containingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G hemi-Tetrahydrofuran (3 g), and the contents were agitated at 50°C. The contents were filtered and washed with THF (3×6 mL). Solids weredried in a vacuum oven at 45° C. with a nitrogen bleed to yield Form O(Anhydrous) (45% yield).

The XRPD scan is shown in FIG. 28 and the peak assignments are in Table28:

TABLE 28 Relative 2θ d (Å) Intensity 8.161 10.825 10.4 8.875 9.9558 69.361 9.4402 4.7 9.96 8.8737 3.5 10.522 8.4007 9.9 11.238 7.8669 10012.722 6.9528 6.4 13.541 6.534 10.6 15.043 5.8845 7.4 15.544 5.6961 8.716.079 5.5079 21 16.52 5.3618 41 17.63 5.0266 5.6 18.701 4.741 6.719.198 4.6193 9.3 19.98 4.4404 36.8 21.243 4.1791 6.8 22.179 4.0048 59.722.677 3.9179 19.2 23.141 3.8405 20.9 24.86 3.5786 18.7 25.638 3.471825.8 26.861 3.3164 8.1 27.979 3.1864 10.1 28.376 3.1427 4.7 30.5832.9208 6 31.917 2.8017 4.5 32.657 2.7398 2.2 33.861 2.6451 5.3

Example 29N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm P

Water (12 mL) was added to a vial containingN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm G Tetrahydrofuran (1.5 g), and the contents were agitated at roomtemperature. The contents were filtered and washed with THF:water (1:2.2v/v. 7.2 mL) and water (7.2 mL). The wet cake was dried in a vacuum ovenat 55° C. with a nitrogen bleed to yield Form P (Anhydrous) (81% yield).

The XRPD scan is shown in FIG. 29 and the peak assignments are in Table29:

TABLE 29 Relative 2θ d (Å) Intensity 6.962 12.687 5.1 9.901 8.9266 38.511.043 8.0059 25.4 11.422 7.7411 1.4 12.48 7.0867 1.7 13.123 6.7412 6.913.74 6.4396 28.6 14.577 6.0716 10.9 15.403 5.7481 20.5 15.662 5.653648.4 16.424 5.3929 13.9 17.661 5.0179 32 18.777 4.7221 6.7 19.92 4.45378.1 20.541 4.3204 22.4 21.684 4.0951 4.3 22.14 4.0118 11.7 23.04 3.85714.6 23.5 3.7826 100 24.271 3.6641 1.8 24.76 3.5929 17.9 25.359 3.50938.3 26.982 3.3018 10.3 27.619 3.2271 11.9 28.419 3.138 5.2 29.022 3.07426.1 29.923 2.9837 9.1 30.781 2.9024 6.3 31.72 2.8186 4.6 32.044 2.7909 332.314 2.7682 2.2 33.441 2.6774 3.2 34.377 2.6066 5.8 35.815 2.5052 2.636.376 2.4678 3.4 37.083 2.4224 2.1 38.365 2.3443 1.8 38.827 2.3175 2.139.437 2.283 3.1

Example 30 AmorphousN4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine

N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamineForm B Ethanol (402 mg) was added to a vial containing 3:7 water:THF (40mL). The solution was sonicated and stirred until all the solids weredissolved. The solution was then frozen in a dry ice/acetone bath (4hours) and lyophilized over a period of 48 hours to yield an amorphouspowder.

The XRPD scan is shown in FIG. 30 .

Example 31 Pharmaceutical Composition

A pharmaceutical composition may be prepared by forming a powder incapsule (“PIC”) composition containing 25 mg or 100 mg ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diaminefrom Examples 1 to 30. The PIC composition may be prepared in size 00white opaque hard gelatin capsules.

It will be understood that the enumerated embodiments are not intendedto limit the invention to those embodiments. On the contrary, theinvention is intended to cover all alternatives, modifications andequivalents, which may be included within the scope of the presentinvention as defined by the claims. Thus, the foregoing description isconsidered as illustrative only of the principles of the invention.

The words “comprise,” “comprising,” “include,” “including,” and“includes” when used in this specification and in the following claimsare intended to specify the presence of stated features, integers,components, or steps, but they do not preclude the presence or additionof one or more other features, integers, components, steps, or groupsthereof.

1. A crystalline polymorph ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diaminefreebase.
 2. A method of treating cancer in a mammal in need thereof,comprising administering to the mammal an effective amount of acrystalline polymorph ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diaminefreebase.
 3. The method of claim 2, wherein the cancer is a ErbB2positive cancer.
 4. The method of claim 3, wherein the ErbB2 cancer isbreast, colorectal, gastric, or esophageal cancer.
 5. The method ofclaim 2, wherein one or more additional compounds having anti-cancerproperties are administered in combination.
 6. The method of claim 2,wherein the mammal is a human.
 7. The method of claim 3, wherein one ormore additional compounds having anti-cancer properties are administeredin combination.
 8. The method of claim 3, wherein the mammal is a human.9. The method of claim 4, wherein one or more additional compoundshaving anti-cancer properties are administered in combination.
 10. Themethod of claim 4, wherein the mammal is a human.